LTP and LTD in cortical GABAergic interneurons: Emerging rules and roles

Neuropharmacology 60 (2011) 712e719

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Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm

Invited review

LTP and LTD in cortical GABAergic interneurons: Emerging rules and roles Dimitri M. Kullmann a, *, Karri P. Lamsa b a b

UCL Institute of Neurology, Department of Clinical Neurology, Queen Square, London WC1N 3BG, United Kingdom Department of Pharmacology, Oxford University, Mansfield Road, Oxford OX1 3QT, United Kingdom

a r t i c l e i n f o

a b s t r a c t

Article history: Received 10 October 2010 Received in revised form 2 December 2010 Accepted 15 December 2010

Recent studies of excitatory transmission in cortical interneurons reveal a surprising diversity of forms of long-term plasticity. LTP and LTD can be elicited at many synapses on interneurons, and pharmacological manipulations implicate NMDA, calcium-permeable AMPA and metabotropic receptors in the induction of plasticity. Distinct patterns are beginning to emerge in identified pathways, as defined by the cells of origin of the presynaptic glutamatergic axons and the postsynaptic interneuron subtypes. We review this literature, and speculate about the possible adaptive significance of long-term activity-dependent changes in transmission for cortical information processing. This article is part of a Special Issue entitled ‘Synaptic Plasticity & Interneurons’. Ó 2010 Elsevier Ltd. All rights reserved.

Keywords: Interneurons Plasticity AMPA receptors NMDA receptors

1. Introduction Although long-term plasticity in inhibitory circuits of the brain was first reported almost three decades ago (Buzsaki and Eidelberg, 1982), it has only recently received close attention (reviewed by Kullmann and Lamsa, 2007; Pelletier and Lacaille, 2008). This slow start can largely be explained by the need to overcome two obstacles. First, relatively simple recording methods such as extracellular field potential measurements, which have played a central role in understanding the fundamental biology of longterm potentiation and depression (LTP and LTD) in pyramidal neurons, do not easily lend themselves to study changes in synaptic strength in relatively sparse interneurons. Second, GABAergic interneurons constitute a highly diverse population (Ascoli et al., 2008), and if sampled randomly these cells may not reveal consistent patterns of response to defined plasticity induction stimuli. Much of the recent progress can be attributed to an improved understanding of interneuron diversity and to methodological advances, in particular infrared video microscopy coupled with epifluorescence imaging and visually guided patch-clamp. The new results have substantially increased our understanding of the complexity of inhibition, and have led to the recognition that excitatory synapses on interneurons are far more plastic than previously appreciated (McBain et al., 1999). Importantly, some clues are emerging that different synapses in cortical and

* Corresponding author. E-mail address: [email protected] (D.M. Kullmann). 0028-3908/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2010.12.020

subcortical interneurons exhibit characteristic patterns of plasticity, with respect to the conjunctions of pre- and postsynaptic activity that induce changes in synaptic strength, the roles of different receptor systems and signaling cascades, and the mechanisms of expression of LTP and LTD. In this overview we have set ourselves two main tasks, first to identify consistent patterns of plasticity that span across defined populations of interneurons in different brain regions (see Fig. 1 and Tables 1e3), and second to speculate about the potential adaptive significance of these phenomena. From the outset we concede that it is not possible to accommodate all published observations into a simple scheme, and that some of the hypotheses regarding the roles of LTP and LTD in interneurons are highly conjectural. 2. Different forms of plasticity of inhibition Plasticity of inhibitory signaling in the brain is not an exclusive property of the excitatory synapses innervating interneurons. Indeed, activity-dependent changes have been reported both in the strength of GABAergic synapses and in the mechanisms that determine the [Cl
] equilibrium potential in pyramidal neurons (Lamsa et al., 2010). However, long-term plasticity at glutamatergic synapses on interneurons potentially has different consequences for circuit computations because of the complementary roles and connectivities of different sub-types of GABAergic neurons (Klausberger and Somogyi, 2008). Distinct interneurons target different cell types (principal cells, other interneurons) and subcellular compartments (axon initial segments, cell bodies, proximal

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Fig. 1. LTP and LTD of glutamatergic synapses on GABAergic inhibitory interneurons in the brain. Numbers refer to sections in Tables 1e3, which summarize the main phenomenology and mechanisms that have been reported in rodents.

and distal dendrites) (Ascoli et al., 2008). They also evoke inhibitory postsynaptic potentials (IPSPs) with widely different kinetics, and in some cases can depolarize postsynaptic neurons (Szabadics et al., 2006; Ben-Ari et al., 2007). It therefore follows that activitydependent changes in the strength of glutamatergic synapses recruiting them may have different consequences for the dendritic integration of excitatory signals in their postsynaptic targets (Hao et al., 2009), for the initiation of action potentials (Mittmann and Hausser, 2007), for the temporospatial structure of population activity (Dragoi et al., 2003), for information flow in the network (Sohal et al., 2009), and ultimately for behaviour (Robbe and Buzsaki, 2009). A further layer of complexity comes from the finding that LTP in several interneuron types can exhibit synapse specificity. That is, when an induction protocol is delivered to one population of excitatory axons, this can result in an increase in synaptic strength that is confined to the same pathway, leaving unchanged a second, control, pathway that was not stimulated (Lamsa et al., 2005, 2007b; Sambandan et al., 2010; although see also Cowan et al., 1998). Whether LTD also shows synapse specificity is less clear, with some reports arguing that this form of plasticity spreads to other synapses converging on the same interneurons (McMahon and Kauer, 1997; Cowan et al., 1998). Synapse specificity of LTP in interneurons is unexpected in a sense that these cells tend to be devoid of dendritic spines (or only have sparse spines), which have been speculated to be necessary to compartmentalize intracellular signaling. However, synaptically activated calcium signals can show tight compartmentalization in smooth interneuron dendrites (Goldberg et al., 2003; Goldberg and Yuste, 2005). From a computational perspective, synapse-specific LTP implies that the relative strength of excitatory synapses converging upon a population of interneurons from different principal cells is amenable to independent use-dependent changes, thus dynamically altering how they sample activity in their inputs. 3. Plasticity depends on interneuron type in the hippocampal formation As mentioned above, some of the inconsistencies in early reports on the induction of LTP or LTD in interneurons are potentially explained by the fact that these studies either examined different populations of cells or pooled together several subpopulations of interneurons. The criteria used to classify these cells differ among the published reports, and have variably included

electrophysiological, anatomical and immunohistological parameters. Indeed, there is as yet no definitive and universally agreed taxonomy of interneuron types that can be used to cross-reference the different reports systematically (Ascoli et al., 2008). Nevertheless, several recent studies that have used multiple criteria to classify interneurons show that different forms of long-term plasticity can conform to quite consistent rules within distinct cell types. Thus, NMDA receptor-independent LTP can be elicited in interneurons in stratum oriens of the hippocampal area CA1 (Perez et al., 2001), which are innervated by axon collaterals of local pyramidal cells (Blasco-Ibanez and Freund, 1995), but this phenomenon typically does not occur at synapses on interneurons in stratum radiatum (Lamsa et al., 2007a). Oren et al. (2009) recently applied stringent criteria to identify one cell type, orienslacunosum moleculare (O-LM) interneurons in stratum oriens, and systematically tested different induction protocols while recording from the neurons with the perforated patch method to minimize perturbation of the intracellular milieu. O-LM cells are relatively easy to identify because their somata are located in stratum oriens, with dendrites oriented parallel to the pyramidal cell layer, and an axon projecting through stratum radiatum to lacunosum-moleculare where it arborizes profusely. These neurons are also immunopositive for somatostatin and the metabotropic glutamate receptor mGluR1a (Baude et al., 1993; Blasco-Ibanez and Freund, 1995; Maccaferri and McBain, 1995). Oren et al. (2009) showed that LTP could be consistently elicited with high-frequency afferent stimulation of axon collaterals of local pyramidal neurons paired with postsynaptic hyperpolarization, and that this was independent of NMDA receptors. A further study (Nissen et al., 2010) extended this to four other identified interneuron types in the CA1 stratum oriens: parvalbumin (PV) or cholecystokinin (CCK) positive basket cells, axo-axonic cells and bistratified cells. Interestingly, although these interneurons are similarly innervated by the axon collaterals of local pyramidal neurons, and contribute to the feedback circuit in CA1, the plasticity rules differed. Axo-axonic and PVpositive basket cells behaved much as did the O-LM cells, but LTP could not be induced in CCK-positive basket cells, and the same high-frequency stimulation protocol evoked NMDA receptor-independent LTD in bistratified cells. In striking contrast to interneurons in stratum oriens, a subset of interneurons in stratum radiatum of CA1 exhibit NMDA receptordependent LTP that requires postsynaptic depolarization for its induction (Lamsa et al., 2005). This form of LTP occurs at Schaffer collateral synapses on these interneurons and shares many features

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Table 1 Principal features of long-term plasticity studies in interneurons of the hippocampal formation summarized in Fig. 1. Abbreviations: AC: adenylate cyclase; AMPARs, NMDARs: AMPA, NMDA receptors; CaMK: Calcium/calmodulin-dependent kinase; CI, CP: calcium-impermeable, calcium-permeable; DG: dentate gyrus; HFS, LFS: high-, low-frequency stimulation; MF: mossy fibers; PKA, PKC: protein kinase A, C; PLC: phospholipase C; PP: perforant path; STDP: spike-timing-dependent plasticity; TRP: transient receptor potential; VGCC: voltage-gated calcium channels; Vm: membrane potential. Area

Type of inhibitory neuron

Induction protocol

Other receptors and signaling cascades involved

Expression site

Unknown

Unknown.

Occurs in synaptically connected granule cell-basket cell pairs and in single synapses excited extracellularly by minimal stimulation. Requires postsynaptic Ca2þ. Involves PKA and PKC.

Presynaptic.

NMDAR activation (Wang and Kelly, 2001; Lamsa et al., 2005). Involves CaMKII activity (Wang and Kelly, 2001).

Postsynaptic (Lamsa et al., 2005).

NMDAR activation. In synapses with CI-AMPARs (Lamsa et al., 2007b). Involves CaMK activity (Lamsa et al., 2007a). Requires NMDARs and CP-AMPARs. Induced when postsynaptic Vm allows simultaneous activation of both receptors (Laezza and Dingledine, 2004).

Probably postsynaptic (Lamsa et al., 2007b).

HFS (100 Hz) tetanic or theta modulated HFS bursts.

NMDAR-independent. Requires CP-AMPAR activation (Lamsa et al., 2007b; Oren et al., 2009; Nissen et al., 2010). Group I mGluR activation is involved (Lamsa et al., 2007b).

Presynaptic (Lamsa et al., 2007b; Oren et al., 2009).

HFs (30 Hz) bursts, also induced by simultaneous activation of MF and PP.

LTP in MF pathway. Requires CP-AMPARs, not NMDARs.

Unknown.

NMDAR-independent. In synapses with CP-AMPARs (Perez et al., 2001). Requires group I mGluR activation (Perez et al., 2001; Lapointe et al., 2004). Postsynaptic Ca2þ (Lapointe et al., 2004), Scr/ERK cascade and TRP channels possibly involved (Topolnik et al., 2006). Preceding mGluR7 activation causes the receptor internalization and consequently HFS elicits LTP (Pelkey et al., 2005, 2008) instead of LTD. Requires AC/PKA (Pelkey et al., 2008). NMDAR-independent, occurs in synapses with CI-AMPARs and requires postsynaptic Ca2þ and VGCCs (Galvan et al., 2008). Involves PKA and PKC (Galvan et al., 2009). The stimulation protocol induces LTD if mGluR1 is blocked (Galvan et al., 2008). This involves Ca2þ release from intracellular stores and IP3.

Increased transmitter release (Perez et al., 2001; Lapointe et al., 2004; Topolnik et al., 2006).

NMDAR-independent. Induced in synapses with CP-AMPARs and depends on Vm. LTD induced only when membrane potential close to resting Vm or hyperpolarized (Laezza et al., 1999). Involves presynaptic mGluR7. Requires NMDARs. In synapses with CI-AMPARs (Lei and McBain, 2002, 2004).

Unknown

1. LTP in hippocampus, role of different glutamate receptors unknown CA1 and DG in vivo Unidentified subpopulation HFS (40 Hz) tetanic. of interneurons (Buzsaki and Eidelberg, 1982). DG Anatomically identified basket HFS (30 Hz) bursts. cells in hilus (excited by mossy fibers) (Alle et al., 2001). 2. LTP in hippocampus, depends on NMDA receptors CA1eCA3 Unidentified subpopulation of CA1 and CA3 interneurons.

CA1

CA3

Unidentified subpopulation of interneurons.

3. LTP in hippocampus, depends on CP-AMPA receptors CA1 Anatomically identified CA1 interneurons; PVþ or fast-spiking basket (Lamsa et al., 2007b; Nissen et al., 2010), axo-axonic (Lamsa et al., 2007b; Nissen et al., 2010) and OLM cells (Lamsa et al., 2007b; Oren et al., 2009). Hilus Fast-spiking cells, some identified as perisomatic targeting and PV þ (Sambandan et al., 2010).

LFS (1e2 Hz) afferent stimulation paired with postsynaptic depolarization. HFS (100 Hz) tetanic.

HFS (100 Hz) tetanic.

4. LTP in hippocampus, depends on metabotropic glutamate receptors Theta modulated HFS CA1 Mainly unidentified (100 Hz) bursts. subpopulation of interneurons, some identified as OLM cells (Perez et al., 2001).

CA3

Unidentified subpopulation of interneurons in str. lucidum (excited by mossy fibers).

HFS (100 Hz) tetanic.

CA3

Unidentified subpopulation of interneurons in str. lacunosummoleculare (excited by mossy fibers).

HFS (100 Hz) tetanic

5. LTD in hippocampus CA3 Unidentified subpopulation of interneurons.

Unidentified subpopulation of interneurons in str. lucidum (excited by mossy fibers). Unidentified subpopulation of interneurons in str. lucidum (excited by mossy fibers).

HFS (100 Hz) tetanic

HFS (100 Hz) tetanic

HFS (100 Hz) tetanic

Requires mGluR7 activation. In synapses with CP-AMPARs. Depends on PKC and postsynaptic Ca2þ (Pelkey et al., 2005) but not NMDARs.

Unknown.

Increased transmitter release (Pelkey et al., 2005).

Presynaptic (Galvan et al., 2008).

Postsynaptic, involves AMPAR trafficking (Lei and McBain, 2004). Reduced transmitter release (Lei and McBain, 2004) Reduced presynaptic P/Q type VGCC function (Pelkey et al., 2006).

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Table 2 Properties of long-term plasticity in interneurons in neocortical areas illustrated in Fig. 1. Area

Type of inhibitory neuron

6. LTP and LTD in visual cortex LTP in mouse visual cortex. PV expressing or fast-spiking anatomically unidentified interneurons (Sarihi et al., 2008). LTD in mouse primary visual cortex in vivo.

Fast spiking interneurons.

7. LTP and LTD in somatosensory cortex LTP and LTD in rat Unidentified somato-sensory cortex. low-threshold-spiking (LTS) interneurons (Lu et al., 2007).

LTD in rat somatosensory cortex.

Unidentified fast-spiking (FS) cells.

LTP in mouse thalamic excitatory fibers onto somato-sensory cortex.

Unidentified interneurons in layer IV (Chittajallu and Isaac, 2010). Experience-driven strengthening of synapses.

Induction protocol

Other receptors and signaling cascades involved

Expression site

Theta modulated HFS (100 Hz) bursts.

Requires mGluR5 but not mGluR1. Independent of NMDARs or VGCC. Involves postsynaptic Ca2þ, PLC and IP3. Plasticity locus not fully identified, either in glutamatergic synapses onto FS cells or in their GABAergic synapses to pyramidal cells. Suggested mechanism: LTD in FS interneurons (Yazaki-Sugiyama et al., 2009).

Probably postsynaptic.

Pre-post STDP order induces LTP in pyramidal cell-LTS interneurons synapses. Requires NMDARs. Post-pre STDP order induces LTD in pyramidal cell-LTS interneuron connections. Requires mGluRs and is NMDAR independent. Both pre-post and post-pre STDP order induce LTD in pyramidal cell-FS interneuron synapses. Requires mGluR1 but NMDAR-independent. Trimming whiskers suppresses development of glutamatergic thalamic fibers onto feedforward interneurons selectively during 2nd postnatal week.

Presynaptic.

Deprivation of visual signal in one eye depresses disynaptic GABAergic inhibition towards pyramidal cells in the open eye ocular dominance area.

Spike-timing dependent plasticity (STDP) protocol in synaptically connected PC-interneuron pairs.

Whisker activation drives strengthening of the input onto interneurons.

in common with LTP at the synapses that the same axons make on pyramidal neurons. However, LTP in stratum radiatum interneurons is independent of Ca2þ/calmodulin-dependent kinase IIa autophosphorylation (Lamsa et al., 2007a). Which interneuron types in stratum radiatum exhibit LTP, and which do not, remains to be determined. Which features of interneurons explain why one or other form of plasticity can be induced? Two attractive candidates are the Ca2þ buffers that are differentially expressed by different interneurons (in particular calbindin, parvalbumin and calretinin), and the glutamate receptors present at the synapses. Postsynaptic Ca2þ chelation abolishes LTP and LTD in hippocampal interneurons (Cowan et al., 1998; Alle et al., 2001). Although a systematic comparison of Ca2þ signaling in different interneurons remains to be undertaken, an imperfect correlation can be detected between the type of plasticity that can be elicited and the type and abundance of glutamate receptors expressed at different synapses. Thus, synapses where NMDA receptor-independent LTP can be elicited are equipped with rectifying AMPA receptors. A causal role for Ca2þ influx through such receptors has been proposed (Lamsa et al., 2007b; Oren et al., 2009), which is consistent with the principle that postsynaptic hyperpolarization should maximize Ca2þ influx during high-frequency stimulation. The preferential induction of LTP when the interneuron is at a relatively negative potential has been termed ‘anti-Hebbian’ to contrast it with ‘Hebbian’ NMDA receptor-dependent LTP. However, group I metabotropic glutamate receptors (mGluRs) are also required, and indeed, LTP can be induced at the same synapses on O-LM cells by theta-burst stimulation patterns together with postsynaptic depolarization when recording in the whole-cell mode (Perez et al., 2001). The

Unknown.

Presynaptic.

Postsynaptic.

Presynaptic.

involvement of group I mGluRs is consistent with expression of mGluR1 and mGluR5 by many interneurons in stratum oriens (Baude et al., 1993; van Hooft et al., 2000; Ferraguti et al., 2004). Exogenous activation of group I mGluRs alone, however, tends to depress excitatory transmission both in stratum oriens and in stratum radiatum interneurons (Le Duigou et al., 2011). Conversely, in interneurons in stratum radiatum where NMDA receptor-dependent LTP can be elicited, the NMDA receptordependent component of excitatory postsynaptic currents (EPSCs) is prominent (Lamsa et al., 2005). Nevertheless, the expression of different types of receptors at synapses does not appear to be the sole determinant of which form of plasticity can be elicited (Nissen et al., 2010). The properties of LTP and LTD in interneurons of the hippocampal formation are summarized in Table 1. As suggested above, some differences in the optimal LTP induction protocols reported by different laboratories probably relate to differences in the recording methods: perforated patch (Lamsa et al., 2005, 2007a,b; Oren et al., 2009; Nissen et al., 2010) versus whole-cell patch-clamp (McMahon and Kauer, 1997; Cowan et al., 1998; Alle et al., 2001; Perez et al., 2001). These differences may also explain why some studies have reported that LTD was observed more commonly than LTP in interneurons in stratum radiatum in response to high-frequency stimulation of Schaffer collaterals (McMahon and Kauer, 1997; Gibson et al., 2008). Nevertheless, a consistent principle emerging from these studies in CA1 is that NMDA receptor-independent plasticity (LTD or LTP) is accompanied by changes in short-term facilitation, transmission failures, trial-to-trial variability (as measured by the coefficient of variation) or sensitivity to use-dependent antagonists, which imply altered presynaptic glutamate release probability. In contrast,

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Table 3 Long-term plasticity in interneurons in subcortical brain areas explained in Fig. 1. Area 8. LTP and LTD in striatum LTP in rat striatum.

Type of inhibitory neuron

Induction protocol

Other receptors and signaling cascades involved

Unidentified GABAergic interneurons in striatum (excited by glutamatergic axons from cortex).

Spike-timing dependent plasticity (STDP) protocol tested by pairing extracellularly-evoked afferent activation and postsynaptic spiking.

Pre-post STDP order induces LTP. Requires NMDARs (Fino et al., 2008).

LTD in rat striatum. 9. LTP in amygdala Rat basolateral amygdala.

10. LTP and LTD in dorsal cochlear nucleus LTP and LTD in mouse auditory system.

Expression site

Post-pre STDP order induces LTD. Requires NMDARs (Fino et al., 2008). Unidentified subpopulation of interneurons in basolateral amygdala (Mahanty and Sah, 1998).

HFS (30 Hz) tetanic

In synapses with CP-AMPARs. Involves postsynaptic Ca2þ but not NMDARs.

Unknown

Cartwheel inhibitory GABAergic interneurons in dorsal cochlear nucleus.

Spike-timing dependent plasticity (STDP) protocol.

Pre-post STDP order induces LTD (Tzounopoulos et al., 2004). LTD involves presynaptic cannabinoid receptors (Tzounopoulos et al., 2007). Pre-post sequence induced LTP when cannabinoid-receptors blocked. Involves CaMKII (Tzounopoulos et al., 2007).

Presynaptic (Tzounopoulos et al., 2007).

NMDA receptor-dependent plasticity is not accompanied by such changes, and is more akin to conventional LTP in pyramidal neurons. Although the pattern emerging in CA1 implies that the receptors and signaling cascades (Topolnik et al., 2006) expressed by the postsynaptic neuron determines in large part whether a synapse has the molecular machinery appropriate for induction of LTP, it is likely that the identity of the presynaptic neuron also plays an important role. This is supported by the finding in CA3 that different synapses converging on the same interneurons can be equipped with either rectifying or non-rectifying AMPA receptors depending on whether they are supplied by mossy fibres or local pyramidal neurons (Toth and McBain, 1998). Although interneurons in CA3 have not been classified as systematically as in CA1, some rules underlying plasticity in this region are also emerging. Several studies have focused on interneurons in different strata, innervated either by pyramidal cell axon collaterals or by mossy fibres, the axons from dentate granule cells, which also make synapses on interneurons in the dentate hilus. Plasticity at these synapses is reviewed elsewhere in this issue (Laezza and Dingledine, 2011; Galvan et al., in this issue; Bartos et al., 2011), so we will limit ourselves to comparing the emerging principles to the rules governing plasticity in CA1. Both CA3 pyramidal neurons and dentate granule cells make two types of synapses on interneurons in stratum radiatum and stratum lucidum of CA3, with distinct forms of LTD elicited by highfrequency stimulation. At synapses equipped with rectifying AMPA receptors, NMDA receptor-independent LTD was accompanied by changes in trial-to-trial fluctuations and/or sensitivity to a competitive AMPA receptor antagonist implying a presynaptic decrease in glutamate release (Laezza et al., 1999; Toth and McBain, 2000; Lei et al., 2003; Laezza and Dingledine, 2004; Lei and McBain, 2004). LTD induction however requires postsynaptic Ca2þ elevation, most simply explained by entry via rectifying AMPA receptors, although an additional role of postsynaptic mGluRs cannot be excluded. Interestingly, presynaptic mGluR7 receptors (a subtype of group III mGluRs) are implicated in the induction, because LTD was prevented by several different antagonists. In contrast, at synapses with non-rectifying AMPA receptors, high-frequency stimulation elicited either LTP or LTD, both of which required NMDA receptors

and resembled NMDA receptor-dependent plasticity in pyramidal neurons, most likely expressed through trafficking or modulation of postsynaptic AMPA receptors (Toth et al., 2000; Laezza and Dingledine, 2004; Lei and McBain, 2004). Although these studies have reported LTD as the commonest outcome, high-frequency mossy fiber stimulation elicits NMDA receptor-independent LTP in another population of interneurons in stratum lacunosum-moleculare (Galvan et al., 2008). Interestingly, blocking mGluR1 converted an LTP-inducing protocol to LTD, implying that the signaling cascades triggered by high-frequency stimulation are coupled to a bi-directional plasticity. In striking contrast to the principle emerging in stratum oriens interneurons, synapses that exhibited NMDA receptor-independent LTP were equipped with non-rectifying AMPA receptors. Although postsynaptic Ca2þ chelation prevented LTP, Ca2þ influx via ionotropic glutamate receptors appears an unlikely trigger for the induction cascade. Instead, the authors showed that blocking L-type Ca2þ channels prevented LTP, suggesting that this route of Ca2þ, together with mGluR1 activity, is necessary for induction. Further evidence that the identity of the presynaptic bouton (and by implication its innervating axon and parent cell body) is a major determinant of the type of plasticity comes from a comparison of mossy fiber and perforant path inputs to fastspiking interneurons at the border of the dentate hilus and granule cell layer (Sambandan et al., 2010). Some of the studied neurons were anatomically analyzed and shown to project axons back to the granule cell layer. They were tentatively identified as mainly parvalbumin-positive basket cells or axo-axonic cells. NMDA receptorindependent LTP was elicited at mossy fiber (but not perforant path) synapses by pairing presynaptic trains of action potentials with postsynaptic depolarization (see also Alle et al., 2001). The synapses that exhibited LTP were further shown to be equipped with rectifying AMPA receptors, blockade of which prevented LTP induction (Sambandan et al., 2010). There remain many interneurons where long-term synaptic plasticity is not easily induced (Lamsa et al., 2007b). For example, in the hippocampal CA1 area CB1 receptor-positive cells do not exhibit robust LTP or LTD when tested with a range of induction protocols (Nissen et al., 2010). It remains to be determined whether specific combinations of neuromodulators that have not

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been tested can still trigger long-term changes in synaptic strength on these cells. 4. Interneuron type-specific plasticity in other cortical areas By comparison with the hippocampal formation, interneuron classification elsewhere in the forebrain is less well developed. Parvalbumin-positive and fast-spiking interneurons are widespread throughout the neocortex and although these two features are not congruent they overlap, and serve to differentiate neurons from low-threshold spiking cells. Interestingly, a dichotomy of LTP emerges in layer 2/3 of the somatosensory or visual cortex. Synapses formed by pyramidal cells on fast-spiking cells have been shown to exhibit NMDA receptor-independent LTP (Sarihi et al., 2008) or LTD (Lu et al., 2007), which is sensitive to group I mGluR blockade. In contrast, synapses on low-threshold cells in somatosensory cortex exhibit NMDA receptor-dependent LTD or NMDA receptor-independent LTP, depending on whether the postsynaptic spike precedes or follows the presynaptic spike (Lu et al., 2007). Although LTP and LTD in the low-threshold cells were accompanied by changes in transmission failure rate and coefficient of variation, these indices of neurotransmitter release were unaffected by LTP and LTD in fast-spiking cells. This represents a striking departure from the general rule emerging in the hippocampal formation, where NMDA receptors couple to postsynaptic expression mechanisms, while NMDA receptor-independent plasticity (in several cases reported in fast-spiking and/or parvalbumin-positive interneurons) is associated with changes in transmitter release. Although interneuron populations in different cortical areas show some similarities in their plasticity properties, generalizations on cell type-specific plasticity should be made with caution (Table 2). Although certain interneuron types can be found in several areas of cortex, different areas show many specialized circuit properties, and it is possible that these region-specific features include the type of plasticity that can occur in interneurons. It is even more difficult to extrapolate interneuron classification systems from the cerebral cortex to subcortical structures, and long-term plasticity in interneurons in the amygdala, striatum and brainstem are considered in depth elsewhere in this special issue (Spampanato et al., 2011; Venance and Fino, submitted for publication; Bender and Trussell). Nevertheless, we have attempted to compare the mechanisms, induction patterns and tentative expression sites of the different forms of LTP and LTD in interneurons in these areas in Table 3. 5. Functions of interneuron plasticity in the brain Although much attention has been given to determining the induction requirements, intracellular cascades, and expression mechanisms of LTP and LTD in interneurons, relatively less consideration has been given to the adaptive significance of these phenomena. An obvious possible role is to balance global changes in excitability in the network: if excitatory transmission to principal cells were increased because of LTP at many synapses, this could theoretically predispose to seizures. If LTP occurred in parallel at excitatory synapses on inhibitory interneurons, this tendency might be mitigated. This hypothesis is however not based on any experimental observations, and even at excitatory synapses on principal cells, there is often a fine balance between those induction stimuli that give rise to LTP and those that result in LTD. Indeed, conjunctions of pre- and postsynaptic spiking, with intervals determined by population oscillations in different parts of the brain, are probably more relevant to plasticity under physiological conditions than barrages of synchronous action potentials in

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multiple afferents, as are commonly used in experimental studies of synaptic plasticity. The hypothesis that plasticity in interneurons somehow ‘balances’ plasticity in principal cells also ignores the complex roles of different subtypes of interneurons in pattern discrimination both in spatial and temporal domains. Instead, it may be more fruitful to capitalize on emerging insights into the complementary roles of distinct types of interneurons in mediating feed-forward or feed-back inhibition, in inhibiting other interneurons, and in synchronizing the firing of populations of neurons. Another emerging principle underlying the organization of inhibition in many parts of the brain is that the receptive fields of interneurons are generally broader than those of principal cells (Poo and Isaacson, 2009; Kerlin et al., 2010). This is potentially relevant to the synapse specificity of LTP that has been documented in several interneurons (Lamsa et al., 2005; Sambandan et al., 2010), because this feature of plasticity provides a mechanism to redistribute functional connectivity in a strongly convergent pathway as a function of pre- and postsynaptic activity of individual neurons. In the relatively simple circuitry of CA1, at least some of the interneurons in stratum radiatum that express NMDA receptordependent LTP mediate disynaptic feed-forward inhibition (Lamsa et al., 2005). This phenomenon plays an important role in maintaining temporally precise signal integration in local pyramidal neurons. If LTP at Shaffer collateral synapses on pyramidal cells was not accompanied by a potentiation of disynaptic inhibition, the temporal precision of action potential generation in response to asynchronous afferent volleys might be compromised. Lamsa et al tested this prediction by pairing Schaffer collateral stimulation with pyramidal cell depolarization to elicit LTP exclusively at the excitatory synapses on the pyramidal cells. In accordance with the prediction, LTP was accompanied by a reduction in the relative size of the disynaptic IPSP compared to the monosynaptic EPSP, and a consequent widening of the time window in which two converging afferent volleys could elicit a spike (Pouille and Scanziani, 2001). When, in contrast, LTP was elicited both in pyramidal cells and in interneurons (by high-frequency stimulation of Schaffer collaterals), the EPSP-IPSP ratio was maintained, and temporal discrimination remained precise. Whether maintenance of temporal fidelity of action potential generation is an important role of NMDA receptor-dependent LTP in other circuits remains to be determined. In the dentate hilus many interneurons that integrate mossy fiber and perforant path inputs powerfully innervate granule cells, thus providing a form of feedback inhibition that is strongly controlled by afferents from the entorhinal cortex. Interestingly, LTP at mossy fibre synapses on these interneurons can be induced by pairing stimulation of the two inputs (Sambandan et al., 2010). This phenomenon would be expected to lead to a long-lasting increase in inhibition of granule cells innervated by the interneurons, which could play a role in pattern separation in the dentate gyrus (Leutgeb et al., 2007; McHugh et al., 2007). The adaptive roles of NMDAR-independent LTP are more puzzling. In many hippocampal interneurons this phenomenon can be induced under conditions where the postsynaptic cell is at or close to resting membrane potential (Lamsa et al., 2007b), consistent with the inward rectifying properties of Ca2þ-permeable AMPA receptors. Indeed, an early study of LTP in hippocampal interneurons in vivo reported that concurrent activation of many afferents is not required for LTP in inhibitory circuits (Buzsaki and Eidelberg, 1982). Understanding the conditions under which anti-Hebbian LTP might be induced under physiological conditions depends on knowing how the membrane potentials of different interneuron types are modulated from moment to moment in distinct brain states. Some interneurons types that exhibit this form of plasticity

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(in particular O-LM cells) have been reported to be silent during sharp-wave ripples, suggesting that powerful inhibition may prevent them from depolarizing in spite of intense activity in pyramidal neurons (Klausberger et al., 2003). If plasticity is indeed elicited in these and other types of interneurons in the feedback circuit, it could subtly modulate the dynamic interplay of neuronal ensembles during network oscillations. For example, LTP and LTD at pyramidal cell synapses onto parvalbumin-positive basket cells might dynamically regulate neuronal ensembles during gamma oscillations, because these interneurons play a pivotal role in the synchronization of principal neurons (Cardin et al., 2009). The subset of presynaptic pyramidal neurons innervating these interneurons whose synapses become potentiated will consequently have a higher probability of recruiting the interneurons in subsequent cycles, and therefore exert a stronger influence on the phase of the network oscillation. Similar considerations apply to O-LM cells in the hippocampus, which also constitute part of a feedback loop, although their intrinsic and synaptic kinetics and dendritic targeting are tuned to theta rather than gamma oscillations. Synaptic plasticity in interneurons may also have important roles in development and in response to large alterations in sensory input. Thus, an important role of plasticity in parvalbumin-positive GABAergic neurons has been proposed in visual cortical plasticity studied by monocular deprivation in juvenile rodents (YazakiSugiyama et al., 2009). Such neurons showed a paradoxical early increase in excitation from afferents mediating information from the occluded eye. The change in response could be reproduced in a simulation by assuming that excitatory synapses on fast-spiking cells are weakened when pre- and postsynaptic spikes coincide, consistent with NMDA receptor-independent LTD elicited with this induction protocol in vitro (Lu et al., 2007). A recent study by Chittajallu and Isaac (2010) similarly reported that sensory experience drives plasticity in inhibitory circuits in thalamic excitatory pathways that target onto feedforward interneurons in somatosensory cortex layer 4. Deprivation of whisker activity in pups selectively suppressed the development of feedforward inhibition during the second postnatal week. In animals with untrimmed whiskers, in contrast, sensory experience strengthened thalamic excitatory connections onto inhibitory interneurons, presumably via an LTP-like mechanism (Chittajallu and Isaac, 2010). 6. Conclusions Precise definition of pre- and postsynaptic neuron identity, in combination with electrophysiological and pharmacological methods, has begun to uncover the rules that determine which form of plasticity occurs in which circuit. Establishing the roles of these phenomena in normal cortical operation, in development and in behavioural adaptation will ultimately require more sophisticated experimental approaches. Nevertheless, the diversity of plasticity in inhibitory circuits cannot be overlooked in attempting to understand the function of cortical circuits. Acknowledgements Relevant work in the authors’ laboratories is supported by the Wellcome Trust, the Medical Research Council and the European Research Council. References Alle, H., Jonas, P., Geiger, J.R., 2001. PTP and LTP at a hippocampal mossy fiberinterneuron synapse. Proc. Natl. Acad. Sci. U.S.A. 98, 14708e14713.

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