The Roles of GABAB Receptors in Cortical Network Activity

Michael M. Kohl� and Ole Paulsen� �

Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK

The Roles of GABAB Receptors in Cortical Network Activity

Abstract Temporally-structured cortical activity in the form of synchronized network oscillations and persistent activity is fundamental for cognitive processes such as sensory processing, motor control, working memory, and consolidation of long-term memory. The roles of fast glutamatergic excitation via AMPA, kainate, and NMDA receptors, as well as fast GABAergic inhibition via GABAA receptors, in such network activity have been studied in great detail. In contrast, we have only recently begun

Advances in Pharmacology, Volume 58 © 2010 Elsevier Inc. All rights reserved.

1054-3589/10 $35.00 10.1016/S1054-3589(10)58009-8

206

Kohl and Paulsen

to appreciate the roles of slow inhibition via GABAB receptors in the control of cortical network activity. Here, we provide a framework for understanding the contributions of GABAB receptors in helping mediate, modulate, and moderate different types of physiological and pathological cortical network activity. We demonstrate how the slow time course of GABAB receptor-mediated inhibition is well suited to help mediate the slow oscillation, to modulate the power and spatial profile of gamma oscillations, and to moderate the relative spike timing of individual neurons during theta oscillations. We further suggest that GABAB recep­ tors are interesting therapeutic targets in pathological conditions where cortical network activity is disturbed, such as epilepsy and schizophrenia.

I. Introduction The many billions of neurons in the neocortex of the mammalian brain are heavily interconnected through chemical synapses, thereby creating a vast neuronal network. This network is arranged into many individual processing units known as microcircuits, allowing massive parallel proces­ sing of information. Microcircuits comprise sets of precisely intercon­ nected excitatory and inhibitory neurons, and it is a fundamental challenge to understand how these microcircuits operate. Cortical microcircuits form feedforward and feedback loops that gen­ erate spontaneous oscillatory activity, such as the slow oscillation during slow-wave sleep and the fast gamma oscillation during attention. It is likely that these oscillatory modes of network activity are fundamental to the normal function of these local microcircuits. Conversely, when these net­ work activities are disturbed, pathology arises. Interference with the slow oscillation, for example, can lead to memory deficits and generalized epilepsy, and schizophrenia is associated with changes in gamma oscillations. Thus, it is imperative that we study the normal synaptic function of microcircuits. To date, most studies have focused on the roles of fast excitation mediated by AMPA, kainate, and NMDA receptors and fast inhibition mediated by GABAA receptors in the control of network activ­ ity. Much less is understood about the roles of GABAB receptors. In this chapter, we will discuss recent findings that attribute a significant role of slow inhibition via GABAB receptors to the control of cortical network activity. We will first briefly review the functional properties of GABAB receptor-mediated inhibition, and then discuss its involvement in mediat­ ing, modulating, and moderating cortical network activity, before relating these functions to pathological network events.

GABAB Receptors in Cortical Network Activity

207

II. GABAB Receptors in Cortical Microcircuits A. Localization of GABAB Receptors In the 1980s, a series of elegant studies by Norman Bowery (Bowery, 1993; Bowery et al., 1980; 1981a; 1981b; Bowery et al., 1982, 1983; Wilkin et al., 1981) suggested the existence of a second GABA receptor with a distinct pharmacology from the classical GABAA receptor. This bicuculline­ insensitive GABA receptor was called the GABAB receptor and was later shown to consist of a heterodimer made up of two G-protein-coupled receptor subunits, GABAB1a/b and GABAB2 (Jones et al., 1998; Kaupmann et al., 1998; White et al., 1998; for review see Bowery et al., 2002). The GABAB1a/b subunit is thought to be the site of agonist binding, whilst the GABAB2 subunit activates the G-protein signaling system (Galvez et al., 2001; Robbins et al., 2001), and neither subunit is functional in isolation (Agnati et al., 2003; Bowery et al., 2002). Immunohistochemical studies have localized GABAB receptors to both pre- and postsynaptic elements at both excitatory and inhibitory synapses and mainly in the perisynaptic and extrasynaptic plasma membrane (Gonchar & Burkhalter, 1999; Lopez-Bendito et al., 2002, 2004). The requirement of strong or repetitive extracellular stimulation to induce a GABAB receptormediated inhibitory postsynaptic potential (IPSP; Connors et al., 1988; Dutar & Nicoll, 1988; Thomson & Destexhe, 1999), and the absence of a GABAB receptor-mediated IPSP in paired recordings between synaptically-connected GABAergic interneurons and postsynaptic pyramidal cells (Buhl et al., 1994; Thomson et al., 1996), led to the suggestion that GABAB receptors are activated by spillover of synaptically-released GABA from neighboring synapses (for an early review, see Mody et al., 1994). However, it was later shown that activation of individual cells of a specific subclass of interneuron, the neurogliaform cell, could indeed elicit unitary GABAB receptor-mediated IPSPs (Tamás et al., 2003), although it was recently suggested that these cells still provide mostly non-synaptic, spatially non-specific input to the target cells (Oláh et al., 2009). GABAB receptors exert their inhibitory effect by various means. Postsynaptically, GABAB receptors can open G-protein-coupled inwardlyrectifying potassium (GIRK) channels controlling a slow hyperpolarizing potassium conductance (Fig. 1A; Dutar & Nicoll, 1988; Lüscher et al., 1997). They can also directly inhibit postsynaptic calcium channels (Mintz & Bean, 1993), thereby controlling the generation of dendritic calcium spikes in cortical pyramidal cells (Fig. 1B; Pérez-Garci et al., 2006). On the presynaptic side, GABAB receptors have been found to reduce neurotrans­ mitter release, as originally shown by Bowery and colleagues (Bowery et al., 1980). This was seen both at inhibitory synapses, mediated by synapticallyreleased GABA acting on presynaptic GABAB autoreceptors (Fig. 1C;

208

Kohl and Paulsen

(A)

200 µM phaclofen 5 mV 300 ms control

GABABR

(B)

Ca2+ channel GIRK

50 µM baclofen

pre B1a

C

Ca2+

K+

A

B1b

control

B Ca2+

20 pA 50 ms

+50 mV

post −80 mV GABAAR Cl− channel

pre

(C) 100 pA 50 ms control

Cl−

post

200 µM 2-OH-saclofen

FIGURE 1

GABAB receptor effects through three different mechanisms. (A) Postsynaptically located GABAB receptors can open slow potassium conductances by acting on GIRK channels. The GABAB receptor antagonist phaclofen abolishes the associated slow IPSP. (B) Postsynaptic GABAB receptors can also inhibit postsynaptic dendritic calcium channels. A depolarizing voltage step applied in dendritic voltage-clamp during pharmacological Na+ and K+ channel block reveals calcium currents that are inhibited by the GABAB receptor agonist baclofen. (C) Presynaptically located GABAB autoreceptors can close presynaptic calcium channels and directly inhibit the vesicle release machinery. The GABAB receptor antagonist 2-hydroxy­ saclofen prevents GABAB receptor-mediated paired-pulse depression. Traces in (A), (B), and (C) are modified, with permission, from Dutar & Nicoll (1988), Pérez-Garci et al. (2006), and Davies et al. (1990), respectively.

Davies et al., 1990; Davies et al., 1993), and at excitatory synapses, at which GABA “spillover” from neighboring inhibitory synapses was suggested to mediate heterosynaptic depression of excitatory synaptic transmission (Isaacson et al., 1993; Lei & McBain, 2003). Presynaptic inhibition of transmitter release upon activation of GABAB receptors appears to be mediated primarily through the inhibition of calcium channels (Takahashi et al., 1998), though an additional effect directly on the release apparatus is

GABAB Receptors in Cortical Network Activity

209

also possible (Dittman & Regehr, 1996; Sakaba & Neher, 2003). Presynap­ tic and postsynaptic inhibition appears to be mediated via GABAB receptors with distinct GABAB1 subunits, GABAB1a and GABAB1b, respectively (PérezGarci et al., 2006; Ulrich & Bettler, 2007; Vigot et al., 2006).

B. Functional Role of GABAB Receptors To understand the functional roles of GABAB receptor-mediated inhibi­ tion in network function, it is useful to appreciate the conditions under which GABAB receptors are activated. 1. Conditions That Lead to Presynaptic GABAB Receptor Activation Presynaptic GABAB receptors are found on many feedforward inhibi­ tory neurons where they act as autoreceptors (Thompson et al., 1993; Vigot et al., 2006). They have also been found on glutamatergic terminals where they are thought to exert heterosynaptic effects. Paired pulse activation of inhibitory synapses in the rat hippocampus at 10 Hz was shown to result in a depression of the second IPSP that was partially reversed by GABAB receptor antagonists (Fig. 1B; Davies et al., 1990). This effect was dependent on the stimulus strength, suggesting that GABAB autoreceptor activation requires a sufficient amount of synapticallyreleased GABA to accumulate (Lambert & Wilson, 1994). Given the higher affinity of GABAB receptors for GABA when compared to GABAA receptors, this suggests an extrasynaptic location of GABAB autoreceptors. Subsequently, various other cortical interneurons and hippocampal neurogliaform cells were found to modulate their own axon terminals through the activation of GABAB autoreceptors (Oláh et al., 2009; Price et al., 2005, 2008). In contrast, presynaptic receptors on glutamatergic terminals were shown to be activated by GABA spillover from neighboring inhibitory synapses. Isaacson and colleagues were the first to show that repetitive, but not single, stimulation of inhibitory synapses resulted in a slow presy­ naptic inhibition of excitatory synaptic transmission that was blocked by GABAB receptor antagonists (Isaacson et al., 1993; Oláh et al., 2009). 2. Conditions That Lead to Postsynaptic GABAB Receptor Activation Early studies in the hippocampus suggested that only strong stimulation could evoke GABAB receptor-mediated slow IPSPs (Dutar & Nicoll, 1988). In paired recordings from interneurons and pyramidal cells, only GABAA receptor-mediated events could be evoked (Buhl et al., 1994; Thomson et al., 1996), even with repetitive stimuli (Scanziani, 2000). Yet, addition of a GABA uptake blocker revealed a slow IPSC (Scanziani, 2000). Given the higher affinity of GABAB receptors for GABA, it is conceivable that post­ synaptic GABAB receptors are also located extrasynaptically.

210

Kohl and Paulsen

These findings suggest that in order to activate GABAB receptors, cooperativity among release sites is required. This, however, means that postsynaptic GABAB receptors are only activated during periods of synchro­ nous activity under physiological conditions. Such synchronous activity occurs during network oscillations and studies have shown that the synaptic activation of GABAB receptors during cholinergically-induced theta rhythm in hippocampal slices modulates this oscillation (Scanziani, 2000). Similarly, prolonged burst firing in ferret perigeniculate neurons produced GABAB receptor-mediated slow IPSPs in neurons of the lateral geniculate nucleus (Kim et al., 1997). However, whereas only fast GABAA receptor-mediated events were observed following unitary activation of perisomatic-targeting interneurons (Buhl et al., 1994; Thomson et al., 1996), dendritic-targeting neurogliaform cells have been shown to elicit GABAB receptor-mediated IPSPs following single action potentials in both neocortex (Tamás et al., 2003) and hippocam­ pus (Price et al., 2008), and it has recently been demonstrated that this effect is possibly mediated by volume transmission through the synchronous release of GABA from many boutons of neurogliaform cells (Oláh et al., 2009). In conclusion, it is becoming clear that activation and action of GABAB receptors are very distinct from those of GABAA receptors. GABAB recep­ tors usually require sustained activity for activation, and GABAB receptormediated effects, whether mediated by enhancing potassium conductances or inhibiting calcium channels, are typically long-lasting.

III. Control of Network Activity by GABAB Receptors The sustained synaptic activity required for GABAB receptor activation is usually met during rhythmic network activity or burst firing. This, in combination with GABAB receptor-mediated strong and long-lasting inhi­ bitory effects, implicates GABAB receptors in the regulation of cortical net­ work activity. Depending on the temporal properties of network activity, GABAB receptors can (A) directly mediate slow network activity, (B) modulate the strength of fast network activity, and (C) moderate the relative spike timing of individual cells during network oscillations.

A. GABAB Receptor-Mediated Direct Control of Slow Network Activity 1. Cortex In the early 1990s, Steriade and colleagues identified a slow oscillation (<1 Hz) in the cortex in vivo during anaesthesia and sleep (Steriade et al.,

GABAB Receptors in Cortical Network Activity

211

1993a; Steriade et al., 1993c, 1993d). These slow oscillations show alter­ nating persistently active “Up states” and quiescent “Down states,” each about 1–2 s in duration. Slow oscillations survived extensive thalamic lesions as well as the transection of the corpus callosum (Steriade et al., 1993a, 1993c, 1993d). Furthermore, fully deafferented cortical slabs also exhibited slow oscillations (Timofeev et al., 2000), suggesting that such cortical activity can be generated independently of subcortical input. The finding that slow oscillations are generated intrinsically in the cortex and can persist without thalamic input (Steriade et al., 1993d; Timofeev et al., 2000) enabled the introduction of reduced cortical prepara­ tions in vitro that allowed the study of the mechanisms underlying such persistent activity (Sanchez-Vives & McCormick, 2000; Shu et al., 2003). McCormick and colleagues were the first to develop an acute slice model of the slow oscillation using ferret prefrontal and visual cortex exhibiting spontaneous Up and Down states (Sanchez-Vives & McCormick, 2000; Shu et al., 2003). Subsequently, spontaneous slow oscillations were also observed in thalamocortical slices (MacLean et al., 2005; Rigas & Castro-Alamancos, 2007) and in slices from the rodent entorhinal cortex (Cunningham et al., 2006; Mann et al., 2009). Using these preparations, it was found that the recurrent connectivity in the cortex is sufficient to drive persistent activity (Up states). Fast excitation (AMPA/kainate receptors) and inhibition (GABAA receptors) were found to scale proportionally, prevent­ ing run-away excitation that could otherwise lead to epileptiform activity (Mann et al., 2009; Shu et al., 2003). However, the mechanisms underlying the termination of Up states are less clear. Cell-intrinsic properties and currents have been suggested to form the basis for Up-to-Down-state transitions (Bazhenov et al., 2002; Compte et al., 2003; Hill & Tononi, 2005; Milojkovic et al., 2005). However, the Up-and-Down-state transitions were found to be highly synchronous across the whole cortex, suggesting that a long-range synaptic mechanism might be at play (Volgushev et al., 2006). Using a model of Up and Down states in the rat entorhinal cortex, it was found that GABAB receptors are likely to be part of this mechanism. GABAB receptor block was found to increase Up­ state duration and prevent stimulus-induced Down-state transitions (Mann et al., 2009; Fig. 2A). Over the course of the Up state, the membrane potential steadily dropped and input conductance increased. Additionally, following the Up state, Mann and colleagues observed a pronounced hyper­ polarization, which was associated with a refractory period of up to 10 s during which new Up states could not be initiated. These time courses fit well with a GABAB receptor-mediated IPSP. The GABAB receptor-mediated Up-state termination might be due to presynaptic inhibition, postsynaptic hyperpolarizing currents, and/or the direct inhibition of postsynaptic cal­ cium influx (Pérez-Garci et al., 2006), which could be necessary for the maintenance of Up states. The slow kinetics of GABAB receptors would

212

Kohl and Paulsen

Cortical pyramidal cell

GABABR

-

(A)

10 mV 0.5 s

-

control

−65 mV

+ 1 µM CGP55845

(B)

Nucleus reticularis neuron

-

20 mV 0.5 s

-

GABABR

(C)

Thalamocortical relay cell 25 mV GABABR IPSP 75 ms

-

20 mV 1s

FIGURE 2 GABAB receptor mediation of slow oscillations. (A) GABAB receptors contribute to the termination of Up states. GABAB receptor block with CGP55845 reversibly increases the duration of Up states (left panel) and prevents Up-state termination by extracellular stimulation (arrowhead) in the superficial layers. (B) Slow oscillatory input from the cortex activates thalamic reticular neurons, whose reciprocal inhibition via GABAB receptor-mediated slow IPSPs facilitates rebound bursting. (C) Strong burst activity in thalamic reticular neurons activates GABAB receptors, which produce slow IPSPs in thalamocortical relay neurons (upper trace). The resultant hyperpolarization de-inactivates T-type calcium channels leading to calcium spikes (lower trace) that integrate with the ongoing slow oscillation in the cortex to produce sleep spindles and delta waves. Traces are modified, with permission, from Mann et al. (2009) (A), Steriade et al. (1996) (B), Roy et al. (1984) (C, upper trace) and Vincenzo Crunelli & Hughes (2010) (C, lower trace).

seem to match the slow time course of Up and Down states, allowing GABAB receptors to exert a strong synaptic effect and thereby control the frequency and synchronization of the slow oscillation.

GABAB Receptors in Cortical Network Activity

213

2. Thalamus The slow cortical oscillation provides rhythmic input to thalamic nuclei through corticothalamic projections. Such slow rhythmic input is thought to drive synchronized network activity through reciprocally-connected excita­ tory and inhibitory cells in the thalamus. These oscillations can in turn instruct cortical physiological network activity such as delta waves and sleep spindles, as well as pathological spike-and-wave discharges during generalized absence epilepsy. Thalamocortical neurons and interneurons in the reticular formation both express T-type calcium channels, which mediate a low-threshold Ca2+ current. This Ca2+ current promotes the generation of low-threshold Ca2+ spike-mediated bursts of action potentials. Strong hyperpolarization of these thalamic neurons facilitates the de-inactivation of T-type calcium channels, thereby enhancing the generation of rebound action potential bursts. These bursts are characteristic for thalamic neurons and critical to the generation of normal thalamocortical rhythms, such as spindle waves during slow-wave sleep (Fig. 2B and C). The rebound Ca2+ spike burst activity in thalamic reticular neurons has been shown to depend on recurrent inhibition amongst reticular neurons. This inhibition is mediated by GABAB receptors, which provide sufficient hyperpolarization to drive rebound Ca2+ spike burst activity (Ulrich & Huguenard, 1996). In turn, this burst activity coordinates the generation of rhythmic activity in thalamocortical neurons. Using paired recordings from interneurons in the perigeniculate nucleus (PGN) and thalamocortical neurons in the dorsal lateral geniculate nucleus in acute slices from ferrets, Kim and colleagues dissociated the roles of GABAA and GABAB receptors in the generation of rebound burst activity (Kim et al., 1997). They showed that low-frequency (<100 Hz) discharge of PGN neurons recruits mainly GABAA receptor-mediated fast inhibition controlling the dendritic processing and probability of action potential generation in thalamocortical neurons. In contrast, highfrequency burst activity in PGN neurons resulted in large GABAA receptormediated compound IPSPs that were effective in eliciting rebound Ca2+ spike burst activity. These bursts of action potentials in thalamocortical neurons are essential for the generation of normal thalamocortical rhythms, such as spindle waves (for review, see Steriade et al., 1993b), and, through reciprocal connections, can excite more PGN and thalamic reticular neurons. Finally, prolonged and high-frequency burst discharge of PGN neurons, or perhaps the simultaneous activation of a number of PGN cells, was shown to result in the strong activation of GABAB recep­ tors on thalamocortical neurons (Bal et al., 1995a, 1995b; Huguenard & Prince, 1994). The slow kinetics and prolonged time course of the GABAB receptor-mediated IPSPs (Fig. 2C, lower trace) resulted in the entrainment

214

Kohl and Paulsen

of slow synchronized oscillations, similar to those associated with the generation of spike-and-wave discharges during absence seizures (Crunelli & Leresche, 1991). In summary, activity patterns in thalamocortical cells depend on the amplitude and duration of IPSPs received from thalamic reticular and perigeniculate interneurons. Slow-frequency tonic discharge results in GABAA receptor-mediated IPSPs of small amplitude. Burst activity triggers larger GABAA receptor-mediated IPSPs that enable the generation of rebound Ca2+ spike burst activity in thalamocortical neurons, which is thought to be essential for the generation of normal thalamocortical rhythms. Very strong burst activity in thalamic reticular and perigeniculate GABAergic neurons additionally recruits longer-lasting IPSPs in thalamo­ cortical neurons through the activation of GABAB receptors. This strong inhibition results in the generation of slow synchronized oscillations that may underlie pathological network activity such as spike-and-wave discharges during generalized absence epilepsy (Crunelli & Leresche, 1991).

B. GABAB Receptors Modulate Fast Oscillations Fast network activity occurs at too rapid a time scale for GABAB receptors to mediate this activity directly. However, through their longlasting effects, GABAB receptors are capable of modulating the amplitude of fast oscillations such as gamma oscillations. Gamma oscillations (30–70 Hz) have been associated with a wide range of cognitive processes, ranging from sensory processing (Gray, 1994; Singer, 1993) to memory formation (Fell et al., 2001; Sederberg et al., 2007) and selective attention (Fries et al., 2001), and even consciousness (Llinás et al., 1998). At the cellular level, gamma oscillations appear to be important for the temporal regulation of synaptic activity in the cortex and hippocampus and have thus been associated with a spike timing-dependent form of synaptic plasticity (Traub et al., 1998; Wespatat et al., 2004). Spontaneous gamma oscillations rely on recurrently connected excitatory networks, which can be found in the neocortex, amygdala, and CA3 region of the hippocampus. Gamma oscillations can be induced in vitro by high-frequency stimula­ tion (Sohal et al., 2009; Song et al., 2005; Whittington et al., 1995) and by pharmacological means (Brown et al., 2006; Buhl et al., 1998; Cunningham et al., 2003; Fisahn et al., 2004) in cortical (Cunningham et al., 2003; Sohal et al., 2009; Traub et al., 2005) and hippocampal slices (Brown et al., 2006; Buhl et al., 1998; Fisahn et al., 1998; Hormuzdi et al., 2001; Traub et al., 2000), allowing experimenters to investigate the underlying pharmacological mechanisms.

GABAB Receptors in Cortical Network Activity

215

1. Hippocampus In the hippocampus, gamma oscillations can be recorded in vivo nested within the theta rhythm during exploratory behavior (Bragin et al., 1995; Chrobak & Buzsáki, 1998; Csicsvari et al., 2003; Fell et al., 2001). They have been suggested to contribute to the encoding and retrieval of memory (Bauer et al., 2007; Hasselmo et al., 1996; Montgomery & Buzsáki, 2007; Varela et al., 2001). The mechanisms of hippocampal gamma oscillations have been studied in detail using a number of in vitro models (Fisahn et al., 1998; Fischer et al., 2002; Hájos et al., 2000; Lebeau et al., 2002; Palhalmi et al., 2004; Whittington et al., 1995). It is becoming apparent that rhythmic inhibition provided by fast-spiking, perisomatic-targeting interneurons is crucial for entraining the hippocampal network in the gamma frequency band. Periso­ matic-targeting interneurons are synchronized primarily by collaterals from their targets, CA3 pyramidal cells. It is this recurrent feedback loop that allows local gamma oscillations to control the firing of CA3 pyramidal cells, both spatially and temporally (Mann & Paulsen, 2005). Fast, phasic inhibition through GABAA receptors seems to be an essen­ tial ingredient for the precise control of gamma oscillations. But recent data also implicate GABAB receptors in the control of generating such network activity. GABAB receptor block was shown to prolong stimulus-induced gamma oscillations, suggesting that they could serve as a synaptic control mechanism for fast inhibition-driven network oscillations (Whittington et al., 1995). This idea was expanded by studies using a kainate-based gamma oscillation model (Brown et al., 2007). In this model, transient stimulation was found to suppress re-emergent gamma oscillations for sev­ eral hundred milliseconds, reminiscent of the time course of the GABAB receptor-mediated slow IPSP (Davies et al., 1990; Dutar & Nicoll, 1988; Isaacson et al., 1993). When applying paired pulses (1–3.3 Hz), this suppres­ sive effect was smaller for the second pulse, suggesting a further role of GABAB autoreceptors in shaping the postsynaptic GABAB receptormediated inhibition. It has been suggested that the pro-cognitive effects of GABAB receptor antagonists (Getova & Bowery, 1998; Stäubli et al., 1999) could, at least in part, be mediated by the inhibition of GABAB receptormediated suppression of gamma oscillations. 2. Neocortex Similar mechanisms control the emergence of gamma oscillations in the neocortex. Experimental (Atencio & Schreiner, 2008; Buhl et al., 1998; Cardin et al., 2009; Sohal et al., 2009) and computational studies (Börgers et al., 2005; Brunel & Wang, 2003; Cunningham et al., 2004) have shown that coupled networks consisting of interneurons and pyramidal cells can support synchronous network activity. Fast-spiking interneurons have a

216

Kohl and Paulsen

very high probability of connecting to pyramidal cells and thus present a major source of intracortical inhibition (Beierlein et al., 2003; Gonchar & Burkhalter, 1999; Holmgren et al., 2003; Thomson et al., 1996). Paired recordings from fast-spiking interneurons and pyramidal cells in the audi­ tory cortex have shown that pairs with intersomatic distances of less than 50 mm have a very high probability of being reciprocally connected (Oswald et al., 2009). In contrast, at intersomatic distances of 50–100 mm, only about half the pairs were reciprocally connected (Fig. 3A). Selective stimulation of the inhibitory neurons showed that GABAB receptor-mediated inhibition was stronger for the non-reciprocally connected pairs that were further

(A)

PC1

(B)

1 mV PC2 FS PC2

PC1

FS Cell

20 mV nRC pair

(C)

20

Power (spks2)

RC pair

10

0 20

200 ms

Proximal pairs (RC) Distal pairs (nRC)

40

60

Frequency (Hz)

FIGURE 3 GABAB receptor modulation of gamma oscillations. (A) In the auditory cortex, simultaneous whole-cell recordings from fast-spiking interneurons (FS) and pyramidal cells (PC) reveal that for intersomatic distances <50 mm, most inhibitory connections occur in reciprocally-connected (RC) pairs whilst at greater distances, inhibitory connections are equally likely in RC and non-reciprocally connected (nRC) pairs. (B) 80 Hz stimulation of presynaptic FS cells produces a slow IPSP in nRC pyramidal cells, which is mediated by GABAB receptors. (C) A biophysical model shows that FS-induced feedforward gamma oscillations are strongest when the network inputs are confined to a small area and attenuated in distal pyramidal cells through the activation of GABAB receptors. (B) and (C) are modified, with permission, from Oswald et al. (2009).

GABAB Receptors in Cortical Network Activity

217

apart (Fig. 3B). Consistent with other experimental data (Cardin et al., 2009), a computer model based on these data showed that local inputs elicited strong gamma oscillations (Oswald et al., 2009). In contrast, spa­ tially more distributed activity recruited more GABAB receptor-mediated inhibition, resulting in a suppression of the self-emergent gamma activity (Fig. 3C; Oswald et al., 2009). These data suggest that GABAB receptors allow local network activity to be modulated depending on the spatial distribution of afferent sensory input. This is of significance given the topographic mapping of afferent inputs in the sensory cortices. The precise mechanisms by which GABAB receptor activation is spatially segregated is not clear, but different activity patterns in reciprocally connected and non-connected pairs could result in different levels of activity-dependent internalization (Balasubramanian et al., 2004), (de)phosphorylation (Fairfax et al., 2004), or a decrease in expression levels (Vargas et al., 2008). From these data, it becomes clear that GABAB receptor-mediated responses can have a strong modulatory effect on gamma activity in hippo­ campal and neocortical networks.

C. GABAB Receptors Moderate Spike Timing During Hippocampal Theta Activity Theta oscillations (4–10 Hz) have been recorded in the hippocampus and associated cortical regions; they are most consistently present during REM sleep (Jouvet, 1969), as well as during various types of locomotor activities described by the subjective terms “voluntary,” “preparatory,” “orienting,” or “exploratory” (Vanderwolf, 1969). Theta oscillations are thought to provide a temporal metric, enabling the sequential activation of hippocampal and cortical cell assemblies, which is necessary for processes such as memory acquisition, recollection, and spatial orientation (Hasselmo, 2005; Lisman & Buzsáki, 2008). Whilst the circuit elements required to generate theta oscillations are already present in the hippocampus and cortex (Goutagny et al., 2009), theta oscillations are thought to be orchestrated by inhibitory input from subcortical structures. It has been shown that lesions and inactivation of the medial septum and diagonal band of Broca (MS-DBB), structures that provide cholinergic and GABAergic input to the hippocampus and entorhinal cortex, both resulted in the abolition of theta oscillations in all cortical targets, suggesting a major pacemaker role for the MS-DBB (Petsche et al., 1962). Similarly, stimulation of other subcortical nuclei was capable of inducing theta (for review, see Bland, 1986; Buzsáki, 2002). The studies outlined above suggest that GABAA receptor-mediated inhibition is involved in the generation of theta oscillations. This leaves

218

Kohl and Paulsen

GABAB receptors to moderate other tasks during theta activity. However, the precise roles of GABAB receptors in theta oscillations is not clear. Since at least 60% of inhibitory basket cells discharge synchronously during the theta cycle (Csicsvari et al., 1999), it is conceivable that the amount of GABA released could be sufficient to activate GABAB recep­ tors (Dvorak-Carbone & Schuman, 1999; Scanziani, 2000). Indeed, GABAB receptor block during theta oscillations generated in hippocam­ pal slices by muscarinic activation was found to increase the power of the theta oscillation (Konopacki et al., 1997). Similarly, in vivo administra­ tion of the GABAB receptor blocker CGP35348 was shown to increase the power of theta oscillations during walking, and septal GABAB recep­ tor block resulted in an increase in theta harmonics during walking (Leung & Shen, 2007). Since in vivo recordings from hippocampal pyr­ amidal cells have shown that theta oscillations have an amplitude mini­ mum and phase reversal between �75 and �60 mV (Soltesz & Deschênes, 1993; Ylinen et al., 1995), it has been suggested that the hyperpolarization during theta is mediated by chloride rather than potas­ sium currents. This finding makes it likely that, at least in part, the GABAB receptor-mediated effect on theta oscillations is due to presynaptic inhibition. GABAB receptors might also help hippocampal pyramidal cells to keep intrinsic and extrinsic afferent inputs separate. During ongoing theta oscil­ lations synaptic inputs can advance or delay action potentials depending on whether the input arrives at the ascending or descending phase of the theta cycle (Kwag & Paulsen, 2009). Hippocampal CA1 pyramidal cells receive two major inputs: intrinsic input from the CA3 area (Schaffer collaterals) and extrinsic input from the entorhinal cortex (tempero-ammonic input) (Fig. 4A). The tempero-ammonic pathway was found to recruit more GABAB receptor-mediated inhibition resulting in a more pronounced spike delay than for the Schaffer collateral input (Kwag & Paulsen, 2009; Fig. 4B and C). In this way, GABAB receptors might enable pyramidal cells to integrate intrinsic and extrinsic input differently during ongoing theta network activity (Otmakhova & Lisman, 2004). Moreover, various in silico models have emphasized a role for slow inhibition mediated by GABAB receptors during network activity. For instance, a detailed computational model of the CA3 region by Wallenstein and Hasselmo (1997) showed that learning and recall performance is poor in the absence of GABAB receptor-mediated inhibition. They found that GABAB receptors predominantly suppress intrinsic, but not afferent, excita­ tory and inhibitory transmission during the early phases of the theta cycle, allowing for afferent input carrying information about location to be domi­ nant before the waning of this suppression towards the end of the cycle. This would favor recall of the location sequence (Wallenstein & Hasselmo, 1997).

GABAB Receptors in Cortical Network Activity

219

(B)

(A)

+ GABABR

+

−

TA TA SC

+ GABAAR

+

−

SC

TA SC

40 mV 8 nS 100 ms

Delay (ms)

(C) 30

TA SC

20 10

Advancement

0 −10 −20 −30 −200 −150 −100

−50

0

Time of SC (ms)

FIGURE 4 GABAB receptor moderation of spike timing during theta oscillations. (A) Hippocampal CA1 pyramidal cells receive two major excitatory input pathways: Schaffer collaterals (SC) from CA3 pyramidal cells and tempero-ammonic input (TA) from the entorhinal cortex. Feedforward inhibition in SC input is mediated by GABAA receptors whilst feedforward inhibition in TA input is additionally mediated by GABAB receptors. (B) During ongoing theta oscillations, CA1 cells spike reliably at the peak of the oscillation. Synaptic input during the ascending phase of the oscillation advances postsynaptic spikes, whilst input during the descending phase delays the spike (arrow). (C) The slower, but stronger feedforward inhibition mediated by GABAB receptors in TA input results in a larger spike delay than that in SC input. (B) and (C) are modified, with permission, from Kwag & Paulsen (2009).

D. GABAB Receptors in Pathological Network Activity It is becoming apparent that GABAB receptors are essential for the stability of cortical network activity by mediating, modulating, and moder­ ating such activity. This notion is emphasized by the fact that high doses of GABAB receptor antagonists disrupt normal hippocampal and cortical oscillations and

220

Kohl and Paulsen

eventually lead to epiletiform activity (Leung et al., 2005; Vergnes et al., 1997). Similarly, GABAB receptor knock-out mice are prone to developing spontaneous seizures (Prosser et al., 2001; Schuler et al., 2001). Because GABAB receptor activation can directly or indirectly exert a wide range of stimulating and dampening effects on excitatory and inhibitory synaptic transmission, it is not surprising that GABAB receptor antagonism can also have beneficial effects. For instance, in genetically seizure-prone animals, GABAB antagonists can block absence seizures (Hosford et al., 1992; Liu et al., 1992). To understand the role of GABAB receptors in pathology and identify possible therapeutic targets, we will first have to elucidate the precise mechanisms of action. We have seen that GABAB receptors are instrumental in mediating the control of slow cortical and thalamic oscillations, including delta waves and sleep spindles, which are thought to coordinate the reacti­ vation and redistribution of hippocampus-dependent memories to neocor­ tical sites (Diekelmann & Born, 2010). Disturbances to these slow oscillations are known to produce sleeps disorders and associated memory deficits (for review, see Diekelmann & Born, 2010). Severe disruption of the thalamic oscillator can even result in epileptiform activity and is thought to underlie juvenile absence seizures. The defining electroencephalogram activity during absence seizures is a large 3 Hz spikeand-wave complex. The circuitry underlying this spike-and-wave discharge involves the activation of GABAB receptors and is relatively well understood. Recent work using a genetic rat model of absence epilepsy has traced the origin of these seizures to increased excitation in the sensory cortices (Meeren et al., 2005). This activity spreads through the cortex and, via corticothalamic neurons, triggers bursts of action potentials in a large number of inhibitory reticular thalamic neurons. This burst results in a pronounced hyperpolariza­ tion of thalamocortical neurons in the ventrobasal nucleus via GABAB recep­ tors, which, through the deinactivation of T-type calcium currents, results in a slower, more synchronized output that triggers the spike-and-wave discharges in the cortex. These discharges further excite reticular cells, rapidly resulting in the generalization of paroxysmal activity in the whole cortex (for review, see Crunelli & Leresche, 2002). Using biophysical models of the thalamic and cortical neurons during spike-and-wave discharges, it has been shown that the cortical spike part coincides with thalamic burst and the wave component is generated by the GABAB receptor-mediated slow potassium current (Destexhe, 1998). The unique properties of GABAB receptor-mediated inhibition are also thought to underlie the characteristic 3 Hz spike-and-wave discharge. Consistent with these simulations, GABAB receptor agonist application in the ventro­ basal and reticular thalamic nuclei of a rat with spontaneous absence seizures was shown to intensify the cortical discharges (Marescaux et al., 1992). Furthermore, blocking GABAB receptors in the ventrobasal

GABAB Receptors in Cortical Network Activity

221

thalamus, but also in the reticular nucleus (Hosford et al., 1992; Liu et al., 1992) and even in the cortex (Prosser et al., 2001), prevents spike-and-wave discharges in experimental models and thus presents a possible pharmaco­ logical target. Indeed, it is thought that the anti-absence drug clonazepam acts by diminishing GABAB receptor-mediated IPSPs in thalamocortical neurons, thereby reducing their tendency to burst in synchrony (Gibbs et al., 1996; Huguenard & Prince, 1994). These data all suggest a significant role for GABAB receptors in the generation and control of epileptiform activity. This identifies the GABAB receptor as a promising therapeutic target for the treatment of seizures. Furthermore, we have seen that GABAB receptors are also involved in modulating fast network activity, such as gamma oscillations, which in turn are implicated in cognitive processes. Psychiatric disorders such as schizo­ phrenia are linked to changes in gamma activity (Uhlhaas & Singer, 2010), making the modulatory effect of GABAB receptor activation a possible therapeutic target here as well (Kantrowitz et al., 2009). Based on the beneficial effects of weak GABAB receptor antagonism on gamma and theta oscillations, a couple of behavioral studies have reported enhancement of cognitive performance in several different animal species following block­ ade of GABAB receptors (Carletti et al., 1993; Mondadori et al., 1993). Further studies are required to elucidate a possible link between the control of fast oscillations through GABAB receptors and psychiatric disorders associated with disturbed fast oscillations.

IV. Conclusion Since Norman Bowery’s seminal experiments in the 1980s, we have learned a great deal about the effect of GABAB receptor activation at the cellular level. However, the functional role of GABAB receptors at the network level is only just starting to emerge. Here, we have outlined a framework for understanding the contributions of GABAB receptors in helping to mediate, modulate, and moderate different types of physiological and pathological cortical network activity. We have reviewed how GABAB receptor activation in cortical and subcortical structures can help mediate the slow oscillation. Since the disturbance of the slow oscillation is associated with sleep disorders, memory deficits, and the generation of epileptiform activity, GABAB receptors present an attractive therapeutic target for the treatment of these conditions. Moreover, we have reviewed recent literature that implicates GABAB receptors in the modulation of the power and spatial profile of fast network oscillations. These fast oscillations have been associated with cognitive functions, implicat­ ing the GABAB receptor in potential treatments of cognitive disorders. Finally, we also present evidence for a role of GABAB receptors in the moderation of the relative spike timing of individual neurons during theta oscillations,

222

Kohl and Paulsen

thereby attributing GABAB receptors a significant role in the synaptic integra­ tion during large-scale network activity. The diffuse nature of many GABAB receptor-mediated effects presents challenges to the experimental study of the physiological role of these receptors in cortical microcircuits. Recent develop­ ments of optogenetic tools promise to deliver new powerful experimental techniques that will enable more precisely targeted studies of GABAB receptor function in both physiological and pathological cortical network activity. Conflict of interest: The authors declare no conflict of interest.

Abbreviations AMPA GABA IPSP NMDA

a-amino-3-hydroxy-5-methyl­ 4-isoxazolepropionic acid g-aminobutyric acid inhibitory postsynaptic potential N-methyl-D-aspartate

References Agnati, L. F., Ferré, S., Lluis, C., Franco, R., & Fuxe, K. (2003). Molecular mechanisms and therapeutical implications of intramembrane receptor/receptor interactions among hepta­ helical receptors with examples from the striatopallidal gaba neurons. Pharmacological Reviews, 55, 509–550. Atencio, C. A., & Schreiner, C. E. (2008). Spectrotemporal processing differences between auditory cortical fast-spiking and regular-spiking neurons. Journal of Neuroscience, 28, 3897–3910. Bal, T., von Krosigk, M., & McCormick, D. A. (1995a). Role of the ferret perigeniculate nucleus in the generation of synchronized oscillations in vitro. Journal of Physiology, 483, 665–685. Bal, T., von Krosigk, M., & McCormick, D. A. (1995b). Synaptic and membrane mechanisms underlying synchronized oscillations in the ferret lateral geniculate nucleus in vitro. Journal of Physiology, 483, 641–663. Balasubramanian, S., Teissére, J. A., Raju, D. V., & Hall, R. A. (2004). Hetero-oligomerization between GABAA and GABAB receptors regulates GABAB receptor trafficking. Journal of Biological Chemistry, 279, 18840–18850. Bauer, E. P., Paz, R., & Paré, D. (2007). Gamma oscillations coordinate amygdalo–rhinal interactions during learning. Journal of Neuroscience, 27, 9369–9379. Bazhenov, M., Timofeev, I., Steriade, M., & Sejnowski, T. J. (2002). Model of thalamocortical slow-wave sleep oscillations and transitions to activated states. Journal of Neuroscience, 22, 8691–8704. Beierlein, M., Gibson, J. R., & Connors, B. W. (2003). Two dynamically distinct inhibitory networks in layer 4 of the neocortex. Journal of Neurophysiology, 90, 2987–3000.

GABAB Receptors in Cortical Network Activity

223

Bland, B. H. (1986). The physiology and pharmacology of hippocampal formation theta rhythms. Progress in Neurobiology, 26, 1–54. Börgers, C., Epstein, S., & Kopell, N. J. (2005). Background gamma rhythmicity and attention in cortical local circuits: A computational study. Proceedings of the National Academy of Sciences of the United States of America, 102, 7002–7007. Bowery, N. G. (1993). GABAB receptor pharmacology. Annual Review of Pharmacology and Toxicology, 33, 109–147. Bowery, N. G., Bettler, B., Froestl, W., Gallagher, J. P., Marshall, F., Raiteri, M., et al. (2002). International Union of Pharmacology. XXXIII. Mammalian g-aminobutyric acid(B) recep­ tors: structure and function. Pharmacological Reviews, 54, 247–264. Bowery, N. G., Doble, A., Hill, D. R., Hudson, A. L., Shaw, J. S., Turnbull, M. J., et al. (1981a). Bicuculline-insensitive GABA receptors on peripheral autonomic nerve terminals. European Journal of Pharmacology, 71, 53–70. Bowery, N. G., Doble, A., Hill, D. R., Hudson, A. L., Turnbull, M. J., & Warrington, R. (1981b). Structure/activity studies at a baclofen-sensitive, bicuculline-insensitive GABA receptor. Advances in Biochemical Psychopharmacology, 29, 333–341. Bowery, N. G., Hill, D. R., & Hudson, A. L. (1982). Evidence that sl75102 is an agonist at GABAB as well as GABAA receptors. Neuropharmacology, 21, 391–395. Bowery, N. G., Hill, D. R., & Hudson, A. L. (1983). Characteristics of GABAB receptor binding sites on rat whole brain synaptic membranes. British Journal of Pharmacology, 78, 191–206. Bowery, N. G., Hill, D. R., Hudson, A. L., Doble, A., Middlemiss, D. N., Shaw, J., et al. (1980). (–)Baclofen decreases neurotransmitter release in the mammalian CNS by an action at a novel GABA receptor. Nature, 283, 92–94. Bragin, A., Jandó, G., Nádasdy, Z., Hetke, J., Wise, K., & Buzsáki, G. (1995). Gamma (40–100 hz) oscillation in the hippocampus of the behaving rat. Journal of Neuroscience, 15, 47–60. Brown, J. T., Davies, C. H., & Randall, A. D. (2007). Synaptic activation of GABA(b) receptors regulates neuronal network activity and entrainment. European Journal of Neuroscience, 25, 2982–2990. Brown, J. T., Teriakidis, A., & Randall, A. D. (2006). A pharmacological investigation of the role of GLUK5-containing receptors in kainate-driven hippocampal gamma band oscilla­ tions. Neuropharmacology, 50, 47–56. Brunel, N., & Wang, X.-J. (2003). What determines the frequency of fast network oscillations with irregular neural discharges? I. Synaptic dynamics and excitation-inhibition balance. Journal of Neurophysiology, 90, 415–430. Buhl, E. H., Halasy, K., & Somogyi, P. (1994). Diverse sources of hippocampal unitary inhibitory postsynaptic potentials and the number of synaptic release sites. Nature, 368, 823–828. Buhl, E. H., Tamás, G., & Fisahn, A. (1998). Cholinergic activation and tonic excitation induce persistent gamma oscillations in mouse somatosensory cortex in vitro. Journal of Physiol­ ogy, 513, 117–126. Buzsáki, G. (2002). Theta oscillations in the hippocampus. Neuron, 33, 325–340. Cardin, J., Carlén, M., Meletis, K., Knoblich, U., Zhang, F., Deisseroth, K., et al. (2009). Driving fast-spiking cells induces gamma rhythm and controls sensory responses. Nature, 459, 663–667. Carletti, R., Libri, V., & Bowery, N. G. (1993). The GABAB antagonist CGP36742 enhances spatial learning performance and antagonises baclofen-induced amnesia in mice. British Journal of Pharmacology Supplementum, 109, P74. Chrobak, J. J., & Buzsáki, G. (1998). Gamma oscillations in the entorhinal cortex of the freely behaving rat. Journal of Neuroscience, 18, 388–398. Compte, A., Sanchez-Vives, M. V., McCormick, D. A., & Wang, X. -J. (2003). Cellular and network mechanisms of slow oscillatory activity (<1 hz) and wave propagations in a cortical network model. Journal of Neurophysiology, 89, 2707–2725.

224

Kohl and Paulsen

Connors, B. W., Malenka, R. C., & Silva, L. R. (1988). Two inhibitory postsynaptic potentials, and GABAA and GABAB receptor-mediated responses in neocortex of rat and cat. Journal of Physiology (Paris), 406, 443–468. Crunelli, V., & Hughes, S. W. (2010). The slow (<1 hz) rhythm of non-rem sleep: A dialogue between three cardinal oscillators. Nature Neuroscience, 13, 9–17. Crunelli, V., & Leresche, N. (1991). A role for GABAB receptors in excitation and inhibition of thalamocortical cells. Trends in Neurosciences, 14, 16–21. Crunelli, V., & Leresche, N. (2002). Childhood absence epilepsy: genes, channels, neurons and networks. Nature Reviews Neuroscience, 3, 371–382. Csicsvari, J., Hirase, H., Czurkó, A., Mamiya, A., & Buzsáki, G. (1999). Oscillatory coupling of hippocampal pyramidal cells and interneurons in the behaving rat. Journal of Neuroscience, 19, 274–287. Csicsvari, J., Jamieson, B., Wise, K. D., & Buzsáki, G. (2003). Mechanisms of gamma oscilla­ tions in the hippocampus of the behaving rat. Neuron, 37, 311–322. Cunningham, M. O., Davies, C. H., Buhl, E. H., Kopell, N., & Whittington, M. A. (2003). Gamma oscillations induced by kainate receptor activation in the entorhinal cortex in vitro. Journal of Neuroscience, 23, 9761–9769. Cunningham, M. O., Halliday, D. M., Davies, C. H., Traub, R. D., Buhl, E. H., & Whittington, M. A. (2004). Coexistence of gamma and high-frequency oscillations in rat medial entorhinal cortex in vitro. Journal of Physiology, 559, 347–353. Cunningham, M. O., Pervouchine, D. D., Racca, C., Kopell, N. J., Davies, C. H., Jones, R.S.G., et al. (2006). Neuronal metabolism governs cortical network response state. Proceedings of the National Academy of Sciences of the United States of America, 103, 5597–5601. Davies, C. H., Davies, S. N., & Collingridge, G. L. (1990). Paired-pulse depression of monosynaptic GABA-mediated inhibitory postsynaptic responses in rat hippocampus. Journal of Physiology, 424, 513–531. Davies, C. H., Pozza, M. F., & Collingridge, G. L. (1993). CGP 55845a: A potent antagonist of GABAB receptors in the ca1 region of rat hippocampus. Neuropharmacology, 32, 1071–1073. Destexhe, A. (1998). Spike-and-wave oscillations based on the properties of GABAB receptors. Journal of Neuroscience, 18, 9099–9111. Diekelmann, S., & Born, J. (2010). The memory function of sleep. Nature Reviews Neuroscience, 11, 114–126. Dittman, J. S., & Regehr, W. G. (1996). Contributions of calcium-dependent and calciumindependent mechanisms to presynaptic inhibition at a cerebellar synapse. Journal of Neuroscience, 16, 1623–1633. Dutar, P., & Nicoll, R. A. (1988). A physiological role for GABAB receptors in the central nervous system. Nature, 332, 156–158. Dvorak-Carbone, H., & Schuman, E. M. (1999). Long-term depression of temporoammonic­ ca1 hippocampal synaptic transmission. Journal of Neurophysiology, 81, 1036–1044. Fairfax, B. P., Pitcher, J. A., Scott, M.G.H., Calver, A. R., Pangalos, M. N., Moss, S. J., et al. (2004). Phosphorylation and chronic agonist treatment atypically modulate GABAB receptor cell surface stability. Journal of Biological Chemistry, 279, 12565–12573. Fell, J., Klaver, P., Lehnertz, K., Grunwald, T., Schaller, C., Elger, C. E., et al. (2001). Human memory formation is accompanied by rhinal–hippocampal coupling and decoupling. Nature Neuroscience, 4, 1259–1264. Fisahn, A., Contractor, A., Traub, R. D., Buhl, E. H., Heinemann, S. F., & McBain, C. J. (2004). Distinct roles for the kainate receptor subunits GluR5 and GluR6 in kainate­ induced hippocampal gamma oscillations. Journal of Neuroscience, 24, 9658–9668. Fisahn, A., Pike, F. G., Buhl, E. H., & Paulsen, O. (1998). Cholinergic induction of network oscillations at 40 hz in the hippocampus in vitro. Nature, 394, 186–189.

GABAB Receptors in Cortical Network Activity

225

Fischer, Y., Wittner, L., Freund, T. F., & Gähwiler, B. H. (2002). Simultaneous activation of gamma and theta network oscillations in rat hippocampal slice cultures. Journal of Physiology, 539, 857–868. Fries, P., Reynolds, J. H., Rorie, A. E., & Desimone, R. (2001). Modulation of oscillatory neuronal synchronization by selective visual attention. Science, 291, 1560–1563. Galvez, T., Duthey, B., Kniazeff, J., Blahos, J., Rovelli, G., Bettler, B., et al. (2001). Allosteric interactions between GB1 and GB2 subunits are required for optimal GABAB receptor function. EMBO Journal, 20, 2152–2159. Getova, D., & Bowery, N. G. (1998). The modulatory effects of high affinity GABAB receptor antagonists in an active avoidance learning paradigm in rats. Psychopharmacology, 137, 369–373. Gibbs, J. W., Schroder, G. B., & Coulter, D. A. (1996). GABAA receptor function in developing rat thalamic reticular neurons: whole cell recordings of GABA-mediated currents and modulation by clonazepam. Journal of Neurophysiology, 76, 2568–2579. Gonchar, Y., & Burkhalter, A. (1999). Differential subcellular localization of forward and feedback interareal inputs to parvalbumin expressing GABAergic neurons in rat visual cortex. Journal of Comparative Neurology, 406, 346–360. Goutagny, R., Jackson, J., & Williams, S. (2009). Self-generated theta oscillations in the hippocampus. Nature Neuroscience, 12, 1491–1493. Gray, J. A. (1994). A general model of the limbic system and basal ganglia: applications to schizo­ phrenia and compulsive behavior of the obsessive type. Revue Neurologique, 150, 605–613. Hájos, N., Katona, I., Naiem, S. S., MacKie, K., Ledent, C., Mody, I., et al. (2000). Cannabi­ noids inhibit hippocampal GABAergic transmission and network oscillations. European Journal of Neuroscience, 12, 3239–3249. Hasselmo, M. E. (2005). What is the function of hippocampal theta rhythm?—Linking beha­ vioral data to phasic properties of field potential and unit recording data. Hippocampus, 15, 936–949. Hasselmo, M. E., Wyble, B. P., & Wallenstein, G. V. (1996). Encoding and retrieval of episodic memories: role of cholinergic and GABAergic modulation in the hippocampus. Hippocam­ pus, 6, 693–708. Hill, S., & Tononi, G. (2005). Modeling sleep and wakefulness in the thalamocortical system. Journal of Neurophysiology, 93, 1671–1698. Holmgren, C., Harkany, T., Svennenfors, B., & Zilberter, Y. (2003). Pyramidal cell communication within local networks in layer 2/3 of rat neocortex. Journal of Physiology, 551, 139–153. Hormuzdi, S. G., Pais, I., LeBeau, F. E., Towers, S. K., Rozov, A., Buhl, E. H., et al. (2001). Impaired electrical signaling disrupts gamma frequency oscillations in connexin 36-deficient mice. Neuron, 31, 487–495. Hosford, D. A., Clark, S., Cao, Z., Wilson, W. A., Lin, F. H., Morrisett, R. A., et al. (1992). The role of GABAB receptor activation in absence seizures of lethargic (lh/lh) mice. Science, 257, 398–401. Huguenard, J. R., & Prince, D. A. (1994). Intrathalamic rhythmicity studied in vitro: nominal t-current modulation causes robust antioscillatory effects. Journal of Neuroscience, 14, 5485–5502. Isaacson, J. S., Solís, J. M., & Nicoll, R. A. (1993). Local and diffuse synaptic actions of GABA in the hippocampus. Neuron, 10, 165–175. Jones, K. A., Borowsky, B., Tamm, J. A., Craig, D. A., Durkin, M. M., Dai, M., et al. (1998). GABAB receptors function as a heteromeric assembly of the subunits GABABR1 and GABABR2. Nature, 396, 674–679. Jouvet, M. (1969). Biogenic amines and the states of sleep. Science, 163, 32–41. Kantrowitz, J., Citrome, L., & Javitt, D. (2009). GABAB receptors, schizophrenia and sleep dysfunction: A review of the relationship and its potential clinical and therapeutic implica­ tions. CNS Drugs, 23, 681–691.

226

Kohl and Paulsen

Kaupmann, K., Malitschek, B., Schuler, V., Heid, J., Froestl, W., Beck, P., et al. (1998). GABABreceptor subtypes assemble into functional heteromeric complexes. Nature, 396, 683–687. Kim, U., Sanchez-Vives, M. V., & McCormick, D. A. (1997). Functional dynamics of gabaergic inhibition in the thalamus. Science, 278, 130–134. Konopacki, J., Golebiewski, H., Eckersdorf, B., Blaszczyk, M., & Grabowski, R. (1997). Thetalike activity in hippocampal formation slices: the effect of strong disinhibition of GABAA and GABAB receptors. Brain Research, 775, 91–98. Kwag, J., & Paulsen, O. (2009). The timing of external input controls the sign of plasticity at local synapses. Nature Neuroscience, 12, 1219–1221. Lambert, N. A., & Wilson, W. A. (1994). Temporally distinct mechanisms of use-dependent depression at inhibitory synapses in the rat hippocampus in vitro. Journal of Neurophy­ siology, 72, 121–130. Lebeau, F.E.N., Towers, S. K., Traub, R. D., Whittington, M. A., & Buhl, E. H. (2002). Fast network oscillations induced by potassium transients in the rat hippocampus in vitro. Journal of Physiology, 542, 167–179. Lei, S., & McBain, C. J. (2003). GABAB receptor modulation of excitatory and inhibitory synaptic transmission onto rat CA3 hippocampal interneurons. Journal of Physiology (Paris), 546, 439–453. Leung, L. S., Canning, K. J., & Shen, B. (2005). Hippocampal afterdischarges after GABABreceptor blockade in the freely moving rat. Epilepsia, 46, 203–216. Leung, L. S., & Shen, B. (2007). GABAB receptor blockade enhances theta and gamma rhythms in the hippocampus of behaving rats. Hippocampus, 17, 281–291. Lisman, J., & Buzsáki, G. (2008). A neural coding scheme formed by the combined function of gamma and theta oscillations. Schizophrenia Bulletin, 34, 974–980. Liu, Z., Vergnes, M., Depaulis, A., & Marescaux, C. (1992). Involvement of intrathalamic GABAB neurotransmission in the control of absence seizures in the rat. Neuroscience, 48, 87–93. Llinás, R., Ribary, U., Contreras, D., & Pedroarena, C. (1998). The neuronal basis for consciousness. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 353, 1841–1849. Lopez-Bendito, G., Shigemoto, R., Kulik, A., Paulsen, O., Fairen, A., & Lujan, R. (2002). Expression and distribution of metabotropic GABA receptor subtypes GABABR1 and GABABR2 during rat neocortical development. European Journal of Neuroscience, 15, 1766–1778. López-Bendito, G., Shigemoto, R., Kulik, A., Vida, I., Fairén, A., & Luján, R. (2004). Distribu­ tion of metabotropic GABA receptor subunits GABAB1a/b and GABAB2 in the rat hippo­ campus during prenatal and postnatal development. Hippocampus, 14, 836–848. Lüscher, C., Jan, L. Y., Stoffel, M., Malenka, R. C., & Nicoll, R. A. (1997). G protein-coupled inwardly rectifying K+ channels (GIRKS) mediate postsynaptic but not presynaptic trans­ mitter actions in hippocampal neurons. Neuron, 19, 687–695. MacLean, J. N., Watson, B. O., Aaron, G. B., & Yuste, R. (2005). Internal dynamics determine the cortical response to thalamic stimulation. Neuron, 48, 811–823. Mann, E. O., Kohl, M. M., & Paulsen, O. (2009). Distinct roles of GABAA and GABAB receptors in balancing and terminating persistent cortical activity. Journal of Neu­ roscience, 29, 7513–7518. Mann, E. O., & Paulsen, O. (2005). Mechanisms underlying gamma (“40 hz”) network oscilla­ tions in the hippocampus — a mini-review. Progress in Biophysics and Molecular Biology, 87, 67–76. Marescaux, C., Vergnes, M., & Bernasconi, R. (1992). GABAB receptor antagonists: potential new anti-absence drugs. Journal of Neural Transmission. Supplementum, 35, 179–188. Meeren, H., van Luijtelaar, G., Lopes da Silva, F., & Coenen, A. (2005). Evolving concepts on the pathophysiology of absence seizures: the cortical focus theory. Archives of Neurology, 62, 371–376.

GABAB Receptors in Cortical Network Activity

227

Milojkovic, B. A., Radojicic, M. S., & Antic, S. D. (2005). A strict correlation between dendritic and somatic plateau depolarizations in the rat prefrontal cortex pyramidal neurons. Journal of Neuroscience, 25, 3940–3951. Mintz, I. M., & Bean, B. P. (1993). GABAB receptor inhibition of P-type Ca2+ channels in central neurons. Neuron, 10, 889–898. Mody, I., De Koninck, Y., Otis, T. S., & Soltesz, I. (1994). Bridging the cleft at GABA synapses in the brain. Trends in Neurosciences, 17, 517–525. Mondadori, C., Jaekel, J., & Preiswerk, G. (1993). CGP36742: the first orally active GABAB blocker improves the cognitive performance of mice, rats, and rhesus monkeys. Behavioral and Neural Biology, 60, 62–68. Montgomery, S. M., & Buzsáki, G. (2007). Gamma oscillations dynamically couple hippocam­ pal CA3 and CA1 regions during memory task performance. Proceedings of the National Academy of Sciences of the United States of America, 104, 14495–14500. Oláh, S., Füle, M., Komlósi, G., Varga, C., Báldi, R., Barzó, P., et al. (2009). Regulation of cortical microcircuits by unitary GABA-mediated volume transmission. Nature, 461, 1278–1281. Oswald, A.-M.M., Doiron, B., Rinzel, J., & Reyes, A. D. (2009). Spatial profile and differential recruitment of GABAB modulate oscillatory activity in auditory cortex. Journal of Neuroscience, 29, 10321–10334. Otmakhova, N. A., & Lisman, J. E. (2004). Contribution of Ih and GABAB to synaptically induced afterhyperpolarizations in CA1: A brake on the NMDA response. Journal of Neurophysiology, 92, 2027–2039. Palhalmi, J., Paulsen, O., Freund, T. F., & Hajos, N. (2004). Distinct properties of carbacholand DHPG-induced network oscillations in hippocampal slices. Neuropharmacology, 47, 381–389. Pérez-Garci, E., Gassmann, M., Bettler, B., & Larkum, M. E. (2006). The GABAB1b isoform mediates long-lasting inhibition of dendritic Ca2+ spikes in layer 5 somatosensory pyr­ amidal neurons. Neuron, 50, 603–616. Petsche, H., Stumpf, C., & Gogolak, G. (1962). The significance of the rabbit’s septum as a relay station between the midbrain and the hippocampus. I. The control of hippocampus arousal activity by the septum cells. Electroencephalography and Clinical Neurophysiol­ ogy, 14, 202–211. Price, C. J., Cauli, B., Kovacs, E. R., Kulik, A., Lambolez, B., Shigemoto, R., et al. (2005). Neurogliaform neurons form a novel inhibitory network in the hippocampal CA1 area. Journal of Neuroscience, 25, 6775–6786. Price, C. J., Scott, R., Rusakov, D. A., & Capogna, M. (2008). GABAB receptor modulation of feedforward inhibition through hippocampal neurogliaform cells. Journal of Neuroscience, 28, 6974–6982. Prosser, H. M., Gill, C. H., Hirst, W. D., Grau, E., Robbins, M., Calver, A., et al. (2001). Epileptogenesis and enhanced prepulse inhibition in GABAB1-deficient mice. Molecular and Cellular Neuroscience, 17, 1059–1070. Rigas, P., & Castro-Alamancos, M. A. (2007). Thalamocortical Up states: differential effects of intrinsic and extrinsic cortical inputs on persistent activity. Journal of Neuroscience, 27, 4261–4272. Robbins, M. J., Calver, A. R., Filippov, A. K., Hirst, W. D., Russell, R. B., Wood, M. D., et al. (2001). GABAB2 is essential for G-protein coupling of the GABAB receptor heterodimer. Journal of Neuroscience, 21, 8043–8052. Roy, J. P., Clercq, M., Steriade, M., & Deschênes, M. (1984). Electrophysiology of neurons of lateral thalamic nuclei in cat: mechanisms of long-lasting hyperpolarizations. Journal of Neurophysiology, 51, 1220–1235. Sakaba, T., & Neher, E. (2003). Direct modulation of synaptic vesicle priming by GABAB receptor activation at a glutamatergic synapse. Nature, 424, 775–778.

228

Kohl and Paulsen

Sanchez-Vives, M. V., & McCormick, D. A. (2000). Cellular and network mechanisms of rhythmic recurrent activity in neocortex. Nature Neuroscience, 3, 1027–1034. Scanziani, M. (2000). GABA spillover activates postsynaptic GABAB receptors to control rhythmic hippocampal activity. Neuron, 25, 673–681. Schuler, V., Lüscher, C., Blanchet, C., Klix, N., Sansig, G., Klebs, K., et al. (2001). Epilepsy, hyperalgesia, impaired memory, and loss of pre- and postsynaptic GABAB responses in mice lacking GABAB(1). Neuron, 31, 47–58. Sederberg, P. B., Schulze-Bonhage, A., Madsen, J. R., Bromfield, E. B., McCarthy, D. C., Brandt, A., et al. (2007). Hippocampal and neocortical gamma oscillations predict memory formation in humans. Cerebral Cortex, 17, 1190–1196. Shu, Y., Hasenstaub, A., & McCormick, D. A. (2003). Turning on and off recurrent balanced cortical activity. Nature, 423, 288–293. Singer, W. (1993). Synchronization of cortical activity and its putative role in information processing and learning. Annual Review of Physiology, 55, 349–374. Sohal, V., Zhang, F., Yizhar, O., & Deisseroth, K. (2009). Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature, 459, 698–702. Soltesz, I., & Deschênes, M. (1993). Low- and high-frequency membrane potential oscillations during theta activity in CA1 and CA3 pyramidal neurons of the rat hippocampus under ketamine-xylazine anesthesia. Journal of Neurophysiology, 70, 97–116. Song, C., Murray, T. A., Kimura, R., Wakui, M., Ellsworth, K., Javedan, S. P., et al. (2005). Role of a7–nicotinic acetylcholine receptors in tetanic stimulation-induced g oscillations in rat hippocampal slices. Neuropharmacology, 48, 869–880. Stäubli, U., Scafidi, J., & Chun, D. (1999). GABAB receptor antagonism: facilitatory effects on memory parallel those on LTP induced by TBS but not HFS. Journal of Neuroscience, 19, 4609–4615. Steriade, M., Contreras, D., Amzica, F., & Timofeev, I. (1996). Synchronization of fast (30–40 hz) spontaneous oscillations in intrathalamic and thalamocortical networks. Journal of Neuroscience, 16, 2788–2808. Steriade, M., Contreras, D., Curró Dossi, R., & Nuñez, A. (1993a). The slow (<1 hz) oscillation in reticular thalamic and thalamocortical neurons: Scenario of sleep rhythm generation in interacting thalamic and neocortical networks. Journal of Neuroscience, 13, 3284–3299. Steriade, M., McCormick, D. A., & Sejnowski, T. J. (1993b). Thalamocortical oscillations in the sleeping and aroused brain. Science, 262, 679–685. Steriade, M., Nuñez, A., & Amzica, F. (1993c). Intracellular analysis of relations between the slow (<1 hz) neocortical oscillation and other sleep rhythms of the electroencephalogram. Journal of Neuroscience, 13, 3266–3283. Steriade, M., Nuñez, A., & Amzica, F. (1993d). A novel slow (<1 hz) oscillation of neocortical neurons in vivo: Depolarizing and hyperpolarizing components. Journal of Neuroscience, 13, 3252–3265. Takahashi, T., Kajikawa, Y., & Tsujimoto, T. (1998). G-protein-coupled modulation of pre­ synaptic calcium currents and transmitter release by a GABAB receptor. Journal of Neuroscience, 18, 3138–3146. Tamás, G., Lorincz, A., Simon, A., & Szabadics, J. (2003). Identified sources and targets of slow inhibition in the neocortex. Science, 299, 1902–1905. Thompson, S. M., Capogna, M., & Scanziani, M. (1993). Presynaptic inhibition in the hippo­ campus. Trends in Neurosciences, 16, 222–227. Thomson, A. M., & Destexhe, A. (1999). Dual intracellular recordings and computational models of slow inhibitory postsynaptic potentials in rat neocortical and hippocampal slices. Neuroscience, 92, 1193–1215. Thomson, A. M., West, D. C., Hahn, J., & Deuchars, J. (1996). Single axon IPSPs elicited in pyramidal cells by three classes of interneurones in slices of rat neocortex. Journal of Physiology, 496, 81–102.

GABAB Receptors in Cortical Network Activity

229

Timofeev, I., Grenier, F., Bazhenov, M., Sejnowski, T. J., & Steriade, M. (2000). Origin of slow cortical oscillations in deafferented cortical slabs. Cerebral Cortex, 10, 1185–1199. Traub, R. D., Bibbig, A., Fisahn, A., LeBeau, F. E., Whittington, M. A., & Buhl, E. H. (2000). A model of gamma-frequency network oscillations induced in the rat CA3 region by carba­ chol in vitro. European Journal of Neuroscience, 12, 4093–4106. Traub, R. D., Bibbig, A., Lebeau, F.E.N., Cunningham, M. O., & Whittington, M. A. (2005). Persistent gamma oscillations in superficial layers of rat auditory neocortex: experiment and model. Journal of Physiology, 562, 3–8. Traub, R. D., Spruston, N., Soltesz, I., Konnerth, A., Whittington, M. A., & Jefferys, G. R. (1998). Gamma-frequency oscillations: A neuronal population phenomenon, regulated by synaptic and intrinsic cellular processes, and inducing synaptic plasticity. Progress in Neurobiology, 55, 563–575. Uhlhaas, P. J., & Singer, W. (2010). Abnormal neural oscillations and synchrony in schizo­ phrenia. Nature Reviews Neuroscience, 11, 100–113. Ulrich, D., & Bettler, B. (2007). GABA(b) receptors: synaptic functions and mechanisms of diversity. Current Opinion in Neurobiology, 17, 298–303. Ulrich, D., & Huguenard, J. R. (1996). g-aminobutyric acid type B receptor-dependent burstfiring in thalamic neurons: A dynamic clamp study. Proceedings of the National Academy of Sciences of the United States of America, 93, 13245–13249. Vanderwolf, C. H. (1969). Hippocampal electrical activity and voluntary movement in the rat. Electroencephalography and Clinical Neurophysiology, 26, 407–418. Varela, F., Lachaux, J. P., Rodriguez, E., & Martinerie, J. (2001). The brainweb: phase synchronization and large-scale integration. Nature Reviews Neuroscience, 2, 229–239. Vargas, K. J., Terunuma, M., Tello, J. A., Pangalos, M. N., Moss, S. J., & Couve, A. (2008). The availability of surface GABAB receptors is independent of g-aminobutyric acid but controlled by glutamate in central neurons. Journal of Biological Chemistry, 283, 24641– 24648. Vergnes, M., Boehrer, A., Simler, S., Bernasconi, R., & Marescaux, C. (1997). Opposite effects of GABAB receptor antagonists on absences and convulsive seizures. European Journal of Pharmacology, 332, 245–255. Vigot, R., Barbieri, S., Bräuner-Osborne, H., Turecek, R., Shigemoto, R., Zhang, Y., et al. (2006). Differential compartmentalization and distinct functions of GABAB receptor variants. Neuron, 50, 589–601. Volgushev, M., Chauvette, S., Mukovski, M., & Timofeev, I. (2006). Precise long-range synchronization of activity and silence in neocortical neurons during slow-wave oscilla­ tions. Journal of Neuroscience, 26, 5665–5672. Wallenstein, G. V., & Hasselmo, M. E. (1997). GABAergic modulation of hippocampal population activity: sequence learning, place field development, and the phase precession effect. Journal of Neurophysiology, 78, 393–408. Wespatat, V., Tennigkeit, F., & Singer, W. (2004). Phase sensitivity of synaptic modifications in oscillating cells of rat visual cortex. Journal of Neuroscience, 24, 9067–9075. White, J. H., Wise, A., Main, M. J., Green, A., Fraser, N. J., Disney, G. H., et al. (1998). Heterodimerization is required for the formation of a functional GABAB receptor. Nature, 396, 679–682. Whittington, M. A., Traub, R. D., & Jefferys, J. G. (1995). Synchronized oscillations in interneuron networks driven by metabotropic glutamate receptor activation. Nature, 373, 612–615. Wilkin, G. P., Hudson, A. L., Hill, D. R., & Bowery, N. G. (1981). Autoradiographic localiza­ tion of GABAB receptors in rat cerebellum. Nature, 294, 584–587. Ylinen, A., Soltész, I., Bragin, A., Penttonen, M., Sik, A., & Buzsáki, G. (1995). Intracellular correlates of hippocampal theta rhythm in identified pyramidal cells, granule cells, and basket cells. Hippocampus, 5, 78–90.