Electrical stimulation protocols for hippocampal synaptic plasticity and neuronal hyper-excitability: Are they effective or relevant?

Experimental Neurology 204 (2007) 1 – 13 www.elsevier.com/locate/yexnr

Review

Electrical stimulation protocols for hippocampal synaptic plasticity and neuronal hyper-excitability: Are they effective or relevant? Benedict C. Albensi a,c,d,⁎, Derek R. Oliver b , Justin Toupin a,b , Gary Odero c a

b

Dept. of Pharmacology and Therapeutics, Univ. of Manitoba, Canada Dept. of Electrical and Computer Engineering, Univ. of Manitoba, Canada c St. Boniface Research Centre, Univ. of Manitoba, Canada d Centre on Aging, Univ. of Manitoba, Canada

Received 25 September 2006; revised 28 November 2006; accepted 11 December 2006 Available online 20 December 2006

Abstract Long-term potentiation (LTP) of synaptic transmission is a widely accepted model that attempts to link synaptic plasticity with memory. LTP models are also now used in order to test how a variety of neurological disorders might affect synaptic plasticity. Interestingly, electrical stimulation protocols that induce LTP appear to display different efficiencies and importantly, some may not be as physiologically relevant as others. In spite of advancements in our understanding of these differences, many types of LTP inducing protocols are still widely used. In addition, in some cases electrical stimulation leads to normal biological phenomena, such as putative memory encoding and in other cases electrical stimulation triggers pathological phenomena, such as epileptic seizures. Kindling, a model of epileptogenesis involving repeated electrical stimulation, leads to seizure activity and has also been thought of, and studied as, a form of long-term neural plasticity and memory. Furthermore, some investigators now use electrical stimulation in order to reduce aspects of seizure activity. In this review, we compare in vitro and in vivo electrical stimulation protocols employed in the hippocampal formation that are utilized in models of synaptic plasticity or neuronal hyperexcitability. Here the effectiveness and physiological relevance of these electrical stimulation protocols are examined in situations involving memory encoding (e.g., LTP/LTD) and epileptiform activity. © 2006 Elsevier Inc. All rights reserved. Keywords: Synaptic plasticity; Electrical stimulation; Epilepsy; Memory; Protocol

Contents Physical basis of electrical stimulation . . . . . Electrode/neural tissue interface . . . . . . Local impact of stimulation on neural tissue Wider perspective . . . . . . . . . . . . . . Induction of synaptic plasticity . . . . . . . . . Hippocampal synaptic plasticity . . . . . . Long-term potentiation (LTP). . . . . . . . High-frequency potentiation . . . . . . . . Theta burst potentiation. . . . . . . . . . . Primed burst potentiation . . . . . . . . . . Other consequences of protocol choice . . .

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⁎ Corresponding author. St. Boniface Research Centre, Dept. of Pharmacology and Therapeutics, Division of Neurodegenerative Disorders, 351 Tache Ave./Lab 4050, Winnipeg, Manitoba, Canada R2H 2A6. E-mail address: [email protected] (B.C. Albensi). 0014-4886/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.expneurol.2006.12.009

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In vivo LTP . . . . . . . . . . . . . . . . Long-term depression . . . . . . . . . . . Modulation of neuronal excitability . . . . . . Protocols for seizure generation: kindling . Is it kindling or plasticity?. . . . . . . . . Protocols for seizure attenuation. . . . . . Discussion and conclusions . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . .

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Physical basis of electrical stimulation Electrode/neural tissue interface At the core of any stimulation process is the interface between the stimulating electrode and the tissue being stimulated. It is common to model the tissue as an electrolytic cell with charge transfer (current) occurring through the motion of ions (Merrill et al., 2005). The ions may be generated through Faradaic charge transfer at the electrode or already exist within the electrolyte. Where charge transfer in an electrode/tissue system is dominated by the inherent ionic character of the neural tissue, the system will appear capacitive in character. This arises from energy storage at the electrode/electrolyte interface resulting from changes of the ion density adjacent to the electrode that arise from a changing potential (voltage) at the electrode. Simple models of how the ion concentrations in this interface region respond to changes in electrode potential are historically grounded in representations of capacitive charging/ discharging. As such, most of the potential difference between the electrode and an arbitrary reference is considered to occur within two ionic layers surrounding the electrode; ions of opposite charge to the electrode forming the inner layer. This simple electrochemical model is frequently termed the Helmholtz ‘double layer’ (von Helmholtz, 1853). The presence of the ‘double layer’ influences mass (and therefore charge) transport to the electrode; however, this transport is not facilitated by explicit pathways such as ion channels in a bi-phospholipid membrane double layer. This simplified model has been refined to a point where the expected Boltzmann distribution of counter-ion concentration in the electrolyte is readily predicted (Chapman, 1913; Grahame, 1947; Guoy, 1910; Outhwaite, 1970; Stern, 1924). Non-Faradaic processes (charge transfer at the electrode) contribute strongly to charge injection into the electrolyte and the impedances associated with this process must also be considered. The lumped-element character of charge transfer is not as clearly defined and the model must also incorporate the difference in electrical potential (at equilibrium) between the electrode material and electrolyte (tissue), sometimes termed the difference in ‘inner potentials’. Fig. 1 shows a lumped-element representation of this model with the Faradaic and non-Faradaic contributions in parallel with each other and a series resistance associated with all charge transport in the electrolyte (Merrill et al., 2005). In order to completely suppress Faradaic charge

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injection, a capacitive electrode design is required (Guyton and Hambrecht, 1974; Rose et al., 1985). Stimulation between two point electrodes is generally achieved by driving a current through the tissue (electrolyte) between two electrodes. Examples of this may be found in earlier work (Villemagne et al., 2005; Wheeler and Novak, 1986) as well as more contemporary studies (Albensi et al., 2004; Feng and Durand, 2005; Heuschkel et al., 2002; Phinney et al., 2003). The response of the system can be monitored directly from the voltage at the second electrode or, as in a number of studies, the potential at a third location may be monitored (Heuschkel et al., 2002). Such an approach is well suited to multi-electrode array-based measurements. Local impact of stimulation on neural tissue The compatibility of the electrode material is an important consideration in stimulation experiments. Most electrodes are fabricated from gold, platinum or alloys of these noble metals. A recent tabulated summary of material biocompatibility may be found in the review of Merrill et al. (2005). As most stimulation protocols employ Faradaic charge injection, oxidation/reduction chemistry is a routine occurrence at the electrode/neural tissue interface. It is not desirable for the system to be driven such that corrosion of the electrode, an irreversible Faradaic process, results. In monophasic stimulation there is a net buildup of electrochemical species resulting from the Faradaic charge injection as the current between the stimulating electrodes is directed in only one direction. Particular care must be taken at higher frequencies (> 50 Hz)

Fig. 1. Typical lumped-element model. Model of an electrode in contact with neural tissue (electrolyte) showing the Faradaic impedance (ZF) and the difference in inner potentials (ΔVIP) that exists between the electrode and electrolyte in parallel with a capacitance (CDL) associated with the Helmholtz double-layer of ions at the electrode. The resistive character of the electrolyte (tissue) is shown in series with the interfacial elements.

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such as those used for LTP or in clinical deep brain stimulation (Merrill et al., 2005) as there is insufficient recovery time between pulses. This results in a monotonic ratcheting of the effective potential in the tissue and a greater chance of tissue damage that could not occur from single pulse stimulation. As such, many stimulation protocols employ a charge-balanced (biphasic) pulse sequence, driving the current in both directions. The reversal of direction is often accompanied by an interphase delay where no current is driven. It has been argued (Brummer and Turner, 1975) that the symmetry of such a stimulation protocol exploits the reversibility of many electrolytic processes thus reducing the possible build up of toxic species either via corrosion of the electrodes or chemical reactions within the tissue. Wider perspective Electrical stimulation of neural tissue occurs in a wide range of investigations of which the present work represents only a subset. Studies of the response to electric fields (Bikson et al., 2001; Ghai et al., 2000) and magnetic fields have been reported (Hsu et al., 2003). Considerable effort has been devoted to the development of multiple-electrode array-based techniques that seek to engineer a neural slice/silicon microelectronic interface (Fromherz, 2005) as well examples of multi-electrode array investigations involving both planar electrodes in contact with the outer surface of a hippocampal slice (Morin et al., 2005) and electrodes that protrude into the tissue in order to bypass the layer of dead cells at the surface of the slice (Heuschkel et al., 2002). Recent advances in device fabrication techniques, influenced heavily by the microelectronics industry and related technological advancements, have enabled the development of electrodes (and arrays thereof) with flexible substrates (Boppart et al., 1992), novel tip geometries (Snow et al., 2006) and nonmetallic materials such as ceramics (Moxon et al., 2004a,b). Notwithstanding the scope of the ensuing discussion, it is important to recognize that the efficacy of using smaller stimulation pulse amplitudes and/or improvements in long-term measurements may be obtainable through the incorporation of novel electrode materials and fabrication techniques in future work. Induction of synaptic plasticity Hippocampal synaptic plasticity The hippocampal formation is an extremely well studied region of the brain, and the reader is referred to numerous reviews for a recap of this information (Buckley, 2005; Forster et al., 2006; Johnston and Amaral, 1998). Likewise, hippocampal synaptic plasticity has been well described and many excellent reviews have also been written (Albensi, 2001; Albensi and Janigro, 2003; Laroche et al., 2000; Nicoll and Schmitz, 2005; O'Mara et al., 2000; Salin et al., 1996). Processes of synaptic plasticity of course also occur outside of the hippocampus, but other regions are not the focus of this review. The current and most widely accepted model of

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synaptic plasticity that results in long-term synaptic change and possibly memory encoding involves the experimental paradigms of long-term potentiation and depression (LTP/ LTD) (Bear and Malenka, 1994; Lisman, 2003; Lynch, 2004; Nicoll and Malenka, 1999). In LTP, brief high frequency bursts (∼ 100 Hz) lead to a long-lasting increase in the strength of synaptic transmission, whereas prolonged low frequency (∼ 1 Hz) stimulation results in a persistent reduction in synaptic transmission (Bear and Malenka, 1994; Bliss and Collingridge, 1993; Nicoll and Malenka, 1999). Moreover, it is generally accepted that the rise in postsynaptic calcium required for hippocampal CA1 LTP induction is due to the entry of Ca++ via the NMDA receptor complex (Huang and Malenka, 1993), although other sources do have some effect under different conditions. In fact, there are several pathways for elevating postsynaptic Ca++, which include NMDA channels, voltage-dependent calcium channels, α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate (AMPA) channels, release from intracellular stores, and through stimulation of metabotropic glutamate receptors (mGluR) (Greenberg and Ziff, 2001). To date, several studies have attempted to link changes in calcium levels with LTP and LTD (Ismailov et al., 2004; Mizuno et al., 2001; Neveu and Zucker, 1996). For instance, Johnston and colleagues using calcium imaging techniques showed that LTP at all major hippocampal synapses share a common induction mechanism involving an initial rise in postsynaptic [Ca++] (Yeckel et al., 1999). Long-term potentiation (LTP) A major rationale over the years for conducting studies investigating synaptic plasticity was and still is to determine if the experimental paradigm of LTP, a model for synaptic plasticity, is a model that truly represents memory encoding. To this end, considerable effort has been made to evaluate the role of activity-dependent neurochemical and biophysical processes that seem to be associated with both synaptic plasticity and memory (Bailey et al., 1996; Baudry and Lynch, 2001; Bliss and Collingridge, 1993; Kirkwood et al., 1996; Martin et al., 2000; Nicoll and Malenka, 1999; Squire, 1992; Squire et al., 1993). In fact, many past studies have attempted to directly link LTP with memory encoding, but the overwhelming majority of evidence shows indirect associations. However, parallels between hippocampal LTP and behaviorally defined memory have been examined critically and several similarities have been found in both. These include: rapid induction, long-lasting processes, strengthening by repetition, dependence on NMDA receptor activation (in most settings but not all), and correlations of LTP decay with the time course associated with normal forgetting (Otto et al., 1991). The induction of NMDA receptorindependent forms of LTP have also been reported in the mossy fiber region and under other conditions (Cavus and Teyler, 1996). In addition, very recently, two studies have been reported in Science that bring LTP and memory processes closer together. In a study by Whitlock et al. (2006) it was found that one-trial inhibitory avoidance learning in rats produced the

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same changes in hippocampal glutamate receptors as did highfrequency stimulation (HFS)-induced LTP and caused a spatially restricted increase in the amplitude of evoked synaptic transmission (in vivo CA1 hippocampus), suggesting that inhibitory avoidance learning induces LTP in the CA1. In the study by Pastalkova et al. (2006) LTP maintenance in vivo was reversed by a PKMζ inhibitor and produced a persistent loss of 1-day-old spatial memory. Together, these studies provide a direct demonstration that hippocampal LTP is induced by learning (Whitlock et al., 2006) and that the mechanism for maintaining LTP sustains spatial memory (Pastalkova et al., 2006). Another aspect of past studies was to identify electrical stimulation protocols that induce and simulate the physiological conditions that are believed to occur during the formation of new memories. Chemical protocols for inducing LTP (LTPc) also exist and have gained in popularity (Aniksztejn and Ben-Ari, 1995; Otmakhov et al., 2004), where LTPc ensures that a larger proportion of synapses are potentiated, unlike electrical stimulation, which is highly localized and only a small fraction of synapses are activated. LTPc protocols, however, will not be discussed here. In any case, LTP of synaptic transmission is a process that results in a persistent increase in the size of the synaptic component of the evoked response (i.e., recorded from cells or populations of cells), which many think is a reasonable representation of endogenous processes of memory formation. High-frequency potentiation LTP can be typically induced by a so-called high-frequency tetanus, which is a train(s) of 50–100 stimuli (i.e., square pulses— see Fig. 2) at 100 Hz (Bliss and Collingridge, 1993). All LTP protocols to our knowledge to date use only square pulses. However, it was realized that different trains of 100 Hz electrical stimulation, although effective at increasing synaptic transmission long-term (Bliss and Collingridge, 1993; Bliss and Lomo, 1973), may not be effective to the same degree. For example, three trains of 100 Hz stimulation (100 pulses for 1 s repeated 3 times with an interval ranging from ∼0.5 to 10 s; total of 300 pulses), which some consider to be strong stimulation (Vertes, 2005), is effective at producing so-called late LTP that lasts 3 h or more and involves protein synthesis (Frey et al., 1993; Huang and Kandel, 1994; Huang et al., 1994; Matthies and Reymann, 1993). However, in some cases, the intertrain interval for 3 trains of 100 Hz has actually been 10 min, which would presumably change the interpretation of any results involving protein synthesis (Frey et al., 1993; McNair et al., 2006; Sajikumar and Frey, 2004). Whereas, a single 100 Hz train (100 pulses over 1 s) is considered weak stimulation, leads to early LTP (1–3 h), and is protein synthesis-independent (Vertes, 2005). Onehundred hertz protocols (i.e., 100 Hz, for 1 s, at baseline stimulation intensity) have been used and are effective for inducing both NMDA receptor-dependent and NMDA receptorindependent forms of LTP. Importantly, standard HFS patterns appear inherently different than naturally occurring firing patterns of neurons.

Fig. 2. Pulse sequence dimensions. (A) Representation of a 100 Hz square pulse, commonly used for LTP induction. The pulse width = 0.1 ms; interpulse interval = 9.9 ms and the pulse length is 10 ms. (B) Representation of a theta burst stimulation pattern commonly used for LTP induction. This stimulation protocol illustrates four 100 Hz pulses applied in rapid succession, 5 times/s. The pulse width = 0.1 ms (not shown); interpulse interval = 9.9 ms; interburst interval = 169.9 ms; burst length = 200 ms. (C) Representation of a primed burst protocol that is used to induce LTP. The pulse width = 0.1 ms (not shown); interpulse interval = 9.9 ms; interval between primed burst +4 = ∼40 ms; primed burst interval = 170 ms.

For example, it is not certain that hippocampal neurons in the living animal fire at 100 Hz for one full second, making standard HFS protocols questionable. CA1 hippocampal pyramidal cells typically fire for only 30–40 ms bursts of three to four spikes (Feder and Ranck, 1973; Kandel and Spencer, 1961; Kandel et al., 1961; Ranck, 1973). In response to these criticisms, other stimulation protocols (Fig. 3), such as theta burst (Graves et al., 1990; Morgan and Teyler, 2001; Pavlides et al., 1988) and primed burst (Rose and

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during behavior, which is correlated with learning (Hill, 1978; Otto et al., 1991; Ranck, 1973). Theta burst potentiation

Fig. 3. Theta-burst stimulation protocols. Several theta burst stimulation protocols were compared for their effectiveness for inducing LTP. The 200 ms interval indicated inthe figure refers to the time period from the onset of the first pulse in the first burst to the onset of the first pulse in the second burst. Used with permission from Morgan and Teyler (2001).

Dunwiddie, 1986) were developed (discussed below) that appear efficient at eliciting LTP and physiologically closer to what occurs in the hippocampus during episodes of learning and memory in living animals (Table 1). In part, this is based on the observation that the hippocampal electroencephalographic (EEG) waveform in rats was shown to be dominated by a 5 to 12 Hz (theta, θ) frequency, observed when animals are engaged in learning-related exploratory behaviors (Grastyan et al., 1959). In addition, the theta-rhythm has been recorded in the CA1 subfield and the dentate gyrus of the hippocampus (Winson, 1972), and also in Ammon's horn, subiculum, cingulated gyrus, and entorhinal cortex (Furukawa et al., 1996). Interestingly, single nerve cells fire a spike that is in phase with the theta rhythm (Graves et al., 1990). In fact, some CA1 hippocampal pyramidal cells discharge at high-frequency in short bursts phase-locked with an ongoing theta rhythm

To this end, several studies have been conducted to test theta burst protocols. Pavlides et al. (1988) demonstrated in anesthetized rats that LTP was more effectively induced in the dentate gyrus when stimulation trains were delivered on the positive phase of theta (as measured by EEG), whereas trains applied in the trough produced a decrease of synaptic efficacy or had no effect. In a study by Huerta and Lisman (1995), a single burst (4 pulses, 100 Hz) was tested to determine its effectiveness for inducing LTP. Similarly, they found that a single burst given at the peak of theta induced LTP, however the same type of burst given during a trough of the theta oscillation induced LTD. Larson et al. also attempted to determine if patterned stimulation at the theta frequency was optimal for the induction of LTP (Larson et al., 1986). In these experiments, their stimulation protocol consisted of several bursts of 4 pulses at 100 Hz (using an interval between bursts of 0.1, 0.2, 1.0, or 2.0 s). They found that longer intervals produced little potentiation, whereas shorter intervals (around 200 ms) were more effective and produced the greatest potentiation. So what makes theta burst electrical stimulation protocols so effective in LTP induction? A primary characteristic of theta burst protocols is the interburst interval of 200 ms. It appears that this interval is a time period when inhibitory post-synaptic potentials (IPSPs) are difficult to recruit. This is because the refractory period for IPSPs ranges from 200 to 500 ms, a period longer than the interburst interval. Without IPSP recruitment (or feed-forward inhibition), repeated stimulation allows for more effective temporal summation of excitatory post-synaptic potentials (EPSPs).

Table 1 Representative electrical stimulation protocols for inducing synaptic plasticity Protocol type/ expected response

Pulse frequency (Hz)

Total no. of pulses/pulse duration (μs)

No. of bursts/burst duration

Trainsa (i.e., a sequence of bursts)

Intervals

Reference(s)

LFS/LTD LFS/LTD LFS/LTD LFS/no change HFS/LTP HFS/LTP HFS/LTP

1 3 3 10 50 100 100

900/100 900/100 1800/100 900/200 50/200 100/200 300/200

1/15 min 1/5 min 1/10 min 1/90 s 1/1 s 1/1 s 3/1 s

1 1 1 1 1 1 1

(Albensi and Mattson, 2000) (Mockett et al., 2002) (Mockett et al., 2002) (Adams and Dudek, 2005) (Adams and Dudek, 2005) (Hernandez et al., 2005) (Hernandez et al., 2005)

Theta/LTP Theta/LTP

100 100 (repeated at ∼ 5 Hz)

4/100 40/100

1/40 ms 5/40 ms

1 2

Theta/LTP (in vivo) Primed Burst/LTP

400 100

5/150 5 (1 + 4)/100

3/12.5 ms 2 (PB + 4)/∼ 40 ms

1 1

∼ 999.9 ms IPI ∼ 333 ms IPI ∼ 333 ms IPI ∼ 99.8 ms IPI ∼ 19.8 ms IPI 9800 μs IPI 9800 μs IPI 10 s IBI 9900 μs IPI 9900 μs IPI 200 ms IBI 10 s ITI 2–3 s IBI 170 ms PBI

(Morgan and Teyler, 2001) (Morgan and Teyler, 2001)

(Hyman et al., 2003) (Rose and Dunwiddie, 1986; Diamond et al., 1988)

Abbreviations: Hz = hertz; HFS = high frequency stimulation; IBI = interburst interval; IPI = interpulse interval; ITI = intertrain interval; LFS = low frequency stimulation; LTD = long-term depression; LTP = long-term potentiation; min = minutes; ms = milliseconds; No. = number; NR = not reported; PB = primed burst; PBI = prime burst interval (time between first pulse and the onset of 4 pulses of 100 Hz); s = seconds; μs = microseconds. a It should be noted that some investigators use the terms burst and train interchangeably, but we have defined a train to be a sequence of bursts.

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Given that theta burst protocols appeared effective at inducing LTP, studies were also conducted addressing whether or not theta burst protocols were also effective at generating long-lasting LTP. To this end, Nguyen et al. (1994) tested theta burst protocols (3 s of theta: 15 bursts of 4 pulses at 100 Hz; pulse width 50 μs; interburst interval 200 ms) in CA1 mouse hippocampal slices and found that the LTP response (EPSP slope, ∼ 170% of baseline) was maintained out to 180 min post stimulation, whereas LTP induced by 60 Hz for 1 s had decayed back to near-baseline levels by this time point. Unfortunately, Nguyen and Kandel did not test and compare the common 100 Hz HFS protocol in this study. However, in a study by Hernandez et al. the results were more surprising (Hernandez et al., 2005). Here they compared a theta burst protocol (4 pulses, 100 Hz, repeated with 200 ms interburst intervals for up to 100 pulses) to a standard HFS protocol (100 Hz for 1 s). In addition, the total number of pulses applied were changed and compared (40, 100, 200, 300; a 10 s intertrain interval was used for the 200 and 300 pulse sequence conditions) in a CA1 rat hippocampal slice preparation. Under these conditions, they made two interesting observations: a) in slices previously stimulated with short theta burst (i.e., 1 pulse + 4 pulses at 100 Hz repeated with 200 ms interburst intervals; 40 total pulses), the number of pulses in a second phase of theta burst stimulation (either a total of 40 of 300 pulses) determined the magnitude of LTP (administered at 60 min) and b) theta burst stimulation produced greater potentiation than 100 Hz in the early phase of LTP (i.e., within the first 30 min) with protocols having a greater pulse number (i.e., 200 or 300). Together, these studies demonstrate how the specific character of each type of protocol results in different effects on later phase LTP, effects that might ultimately result in differences in gene transcription. Given these results one may wonder if the underlying neurochemical mechanisms for HFS are identical to those for theta burst stimulation. Until recently, little was actually understood about the mechanisms that were responsible for theta burst. Data now show that theta burst stimulation, like HFS, in area CA1 also involves transcription, translation, and protein kinase A (PKA) activation (Nguyen et al., 1994). However, calcium-imaging studies involving HFS versus theta burst in CA1 rat hippocampus demonstrate that during theta burst, the mean time to peak of Ca++ signals was significantly longer, and the mean peak amplitude and area under the Ca++ response were larger than during HFS (Perez et al., 1999). In addition, it has been reported that different calcium sources (e.g., VDCC, intracellular stores) have different thresholds for activation by theta burst trains (i.e., 10 × 100 Hz bursts [5 pulse/ burst] and a 200 ms interburst interval at test pulse intensity) where each calcium source might be tuned to the induction of a different form of LTP (Raymond and Redman, 2002). Primed burst potentiation Another experimental paradigm administered in the CA1 for enhancing synaptic transmission long-term is primed burst (PB) potentiation (Diamond et al., 1988; Rose and Dunwiddie, 1986). In this protocol, typically five pulses are used where

the first pulse precedes the last 4 pulses (at 100 Hz) by 170 ms (see Table 1). Rose and Dunwiddie (1986) were one of the first to report that the PB stimulation protocol enhanced the population spike (PS) amplitude, similar to HFS, where both led to the induction of LTP (i.e., PB-PS 243% baseline; HFSPS 331% baseline). However, at 10 min post-stimulation, PB potentiation resulted in a PS that was decaying at a faster rate (i.e., PB 153% vs. HFS 246%). Follow-up studies by Rose and colleagues (Moore et al., 1993) compared PB to HFS (i.e., at 200 Hz for 1 s) in an experimental setting involving aging and showed that PB produced greater differences in the induction of LTP (% change from baseline population spike amplitude) between young (183%) versus old animals (97.3%) than did HFS (232%—young; 181%—old). It would have been useful for this study to also test a common 100 Hz protocol, but this was not attempted. Regardless, the PB protocol appears more sensitive than the 200 Hz HFS protocol for eliciting differences in LTP induction between young versus old animals. So why is the PB protocol so effective? To answer these questions, Larson and Lynch (1986) conducted a related study around the same time period (1986) as Rose and Dunwiddie (1986) where they posed the hypothesis that a burst of synaptic activity might produce a diffuse “priming” effect, which is maximal 200 ms after the burst and alters the postsynaptic response to the high-frequency activity at any synapses on the target neuron. The experiments were conducted in the CA1 of rat hippocampal slices where 2 different stimulating electrodes were used to activate separate groups of Schaffer-commissural projections that converged onto a common CA1 pyramidal neuron. A short burst was delivered to one set of fibers every 2 s with each burst followed by an identical burst to the other set after a 200 ms delay. From these experiments several aspects were realized. It appeared that priming did require a delay to be effective and that repetitive burst stimulation produces LTP by a simple two-step sequence in which a burst primes the postsynaptic neurons such that synapses activated by a subsequent burst causes a stable modification step. In this report, they suggest the priming burst results in the activation of the NMDA receptor, which then produces a prolongation of the EPSP. This explanation appears to be consistent with Rose and Dunwiddie's observations that the pattern of stimulation is the essential feature of PB stimulation. In particular, Rose and Dunwiddie found that the first stimulus pulse seems to somehow sensitize the cell so that subsequent activation induced persistent changes in synaptic efficacy during a critical period following the first stimulus. As a follow up study, Rose and colleagues (Diamond et al., 1988) conducted a very extensive characterization of PB potentiation where they studied the phenomenon not only in hippocampal slices, but also in the awake animal and used a variety of pharmacological manipulations in order to evaluate the mechanisms of PB induction. Here they made several significant observations: 1) synaptic activation is critical for PB, 2) the involvement of the NMDA receptor is necessary for PB, 3) only 140 or 170 ms intervals (not 10–70 ms or 500–5000 ms) were effective, 4) as

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few as 3 pulses (i.e., 1 + 2) were effective (although 1 + 10 was the most effective), and 5) PB can be induced in the awake animal. A similar PB experiment testing different intervals that was conducted in both the CA1 and dentate subfields of the hippocampal slice similarly found that a short interval such as 200 ms (not 50–100 ms or 350–500 ms) was the most effective interval for PB (i.e., 1 + 6) (Pavlides et al., 1988). Collectively, these studies indicate that PB is as effective or more effective than HFS and that a narrow time window involving specific intervals (140–200 ms), which coincidentally corresponds to 6– 7 Hz (i.e., theta range), induces long lasting changes or LTP. Other consequences of protocol choice Given that different stimulation protocols have been used for LTP, one may wonder about the consequences of pulse sequence variations with regard to the contribution of glutamatergic or GABAergic (gamma-aminobutyric acid) neurons in the induction of LTP since both these neurotransmitter systems play a role in the LTP response. It is of course well known that glutamate acts at excitatory synapses, while GABA acts at inhibitory synapses in the brain. Given this, studies have been conducted to investigate glutamatergic versus GABAergic influences on LTP with regard to frequency dependence. For example, the frequency threshold for LTP induction is increased by the GABAA agonist muscimol, whereas picrotoxin, a GABAA antagonist, decreases this threshold suggesting that the inhibitory influence of local GABA interneurons on LTP induction depends on stimulation frequency (Steele and Mauk, 1999). In addition, Davies et al. (1991) showed that GABA-mediated potentials are rapidly suppressed by HFS and that GABAB autoreceptors regulate the induction of LTP (also see below). Interestingly, it was found that benzodiazepines, which are GABAA modulators, have little or no effect on LTP induced by HFS (Chapman et al., 1998; Seabrook et al., 1997). However, benzodiazepines reduced LTP responses induced by complex trains of 100 Hz (i.e., 10 pulses at 100 Hz followed 30 min later by a train of 4 bursts of 10 pulses at 100 Hz given every 20 s), an effect that was also reversed by benzodiazepine antagonists (Chapman et al., 1998). In addition, GABAA antagonists, such as bicuculline, increased theta burst-induced LTP (Chapman et al., 1998). Taken together, these data suggest that different pulse sequences have the potential to differentially activate neurotransmitter systems involved in LTP induction. In addition it should be appreciated, that both theta burst and PB protocols induce LTP with fewer pulses than HFS protocols or brief 100 Hz trains (i.e., less than 100 pulses). As described above, theta burst consists of a few brief bursts of highfrequency trains with an interburst interval in the theta range. Many theta burst protocols are 10 bursts of 4 shocks (each at 100 Hz) with an interburst interval of 200 ms (at a 5 Hz frequency). Therefore, the advantage of theta burst stimulation over a single tetanus of HFS is that it more closely simulates the physiological activation pattern of nerve cells during theta activity. Likewise in PB stimulation, only a small number of pulses are applied unlike HFS, which presumably is closer to

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normal patterns of activation. For example, an average PB protocol is one pulse followed by a delay of 200 ms (5 Hz) and then by a burst of 4 pulses at a frequency of 100 Hz. Davies et al. (1991) working in the Collingridge lab in 1991 attempted to understand the underlying basis for the effectiveness of theta burst and PB stimulation protocols. In a landmark study, they showed that the initial pulse associated with the priming burst depressed synaptic inhibition via GABA receptors and the subsequent pulses activated the NMDA receptor system. More specifically, the priming phase results in GABA release from inhibitory interneurons, which then feeds back onto GABAB autoreceptors to further inhibit the release of GABA. Given this feedback, autoreceptor activation attenuates GABAergic inhibition in a transient manner. This process is then thought to permit sufficient activation of NMDA receptors for the induction of LTP. So one may ask at this point, which is really more effective, HFS or theta burst or PB? This author has intensively reviewed the literature in this regard and also has talked to other several senior investigators (personal communications). It does appear for the most part that both PB and theta burst protocols are superior to HFS (as discussed above), however, every so often evidence to the contrary is put forth as can be seen in the recent paper by Fox et al. (2006) where HFS was superior to theta burst, however, this study was in vivo and should be considered separately. Secondly, there are many more papers published on theta burst protocols than there are on PB so a fair comparison between these two protocols is not yet appropriate. Collectively, we should remember that these are all only models and that in time perhaps an even more relevant protocol will be realized. In vivo LTP One last aspect that should be discussed is that of frequency selection for in vivo LTP. Protocols have typically ranged from 100 to 400 Hz for inducing in vivo LTP, however, several bursts at 400 Hz appears to be the most popular (Cain et al., 1993; Errington et al., 1995; Holscher et al., 1997; Hyman et al., 2003; Merrill et al., 2005; Namgung et al., 1995; Pavlides et al., 1988). Moreover, it appears that early studies (i.e., before 1977) attempted in vivo LTP with 10–100 Hz (2–20 s trains), but it was observed that these stimuli produced strong frequency potentiation, and in unanesthetized animals the protocols had the potential to produce epileptiform afterdischarges (Barrow et al., 2000; Douglas, 1977). In addition, the behavior of postsynaptic neurons was reported “difficult to monitor or manipulate” when using these protocols (Douglas, 1977). To overcome these obstacles, Douglas and Goddard used typically 8 bursts of 400 Hz and stimulated the perforant pathway of the dentate in unanesthetized living rats (Douglas, 1977; Douglas and Goddard, 1975). The 400 Hz protocols used by Douglas utilized a shorter burst time than the previous protocols (i.e., 2–20 s trains), which was thought to be closer to normal discharge times. However, as mentioned above other studies (Feder and Ranck, 1973; Kandel and Spencer, 1961; Kandel

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et al., 1961; Ranck, 1973) showed that CA1 firing discharges were actually much shorter (i.e., 30–40 ms).

stable late-LTD was induced in vitro for 8 h. Collectively these studies indicate that similar to LTP, different temporal forms of LTD can be induced by varying the LFS intensity.

Long-term depression Modulation of neuronal excitability A more limited number of studies have also attempted to evaluate the effectiveness and/or the relevance of low-frequency electrical stimulation protocols that lead to LTD (Mockett et al., 2002; Sajikumar and Frey, 2003; Sajikumar and Frey, 2004). In one such study, two stimulation frequency protocols were compared using 1 or 3 Hz. In addition, an examination of the number of pulses (i.e., 300, 900, 1200, 1800) was made in relation to the percent change in EPSP slope. Here Mockett et al. (2002) found that 1 train of 1200 pulses (20 min) at 1 Hz was more effective than 1 train of 600 (10 min) or 900 pulses (15 min) at 1 Hz for eliciting robust LTD. Similarly, when 3 Hz was tested, the protocol using 1800 pulses (30 min) was more effective than 300 or 900 pulses at eliciting robust LTD (Fig. 4). However, it is also possible that the so-called LTD elicited by 1200–1800 pulses, may actually be rundown. In other words, the observation could be due to an adaptation or exhaustion of the available synaptic vesicles containing neurotransmitter (perhaps not a true form of synaptic plasticity) which may in effect weaken the health of the slice. In a study involving synaptic tagging, Frey and colleagues (Sajikumar and Frey, 2004) used several different protocols for eliciting either weak or strong LTD. For weak LTD, in one case 900 pulses were used (1 Hz, impulse duration 0.2 ms per half wave; total pulses = 900). Here they found a transient early-LTD was produced. For stronger LTD, they used 900 bursts (1 burst = 3 stimuli at 20 Hz; interburst interval = 1 s; stimulus duration 0.2 ms per half wave; total of 2700 pulses) and found that a

In addition to studies on synaptic plasticity, the hippocampal slice preparation has served as a model of epilepsy and has provided researchers a plethora of information on seizure-like activity related to epilepsy (Bernard and Wheal, 1995; Larson et al., 1986; Rafiq et al., 1995). Epilepsy is a group of heterogeneous syndromes associated with excessive neuronal excitability (Stables et al., 2002). It is beyond the scope of this review to survey literature on epilepsy or models of epilepsy and the reader is encouraged to investigate a number of excellent manuscripts on these topics (Delanty et al., 1998; Jefferys, 2003; Moddel et al., 2005; Stables et al., 2002). Instead this section of the review will concentrate on the various electrical stimulation protocols that have been used to either induce epileptiform activity or to attenuate seizure activity in the hippocampus. The reader should also be aware that a vast literature exists involving studies that have utilized electrical or magnetic stimulation protocols (e.g., transmagnetic stimulation, electric field applications, low or high frequency electrical stimulation) other than the ones described below for attempting to reduce excessive neuronal excitability in sites other than the hippocampus or for other therapeutic purposes, such as deep brain stimulation (DBS) for Parkinson's disease (i.e., for treating tremor, akinesia, rigidity, etc.), vagal nerve stimulation for epilepsy, LFS in the spinal cord or thalamus for pain, HFS/DBS for headaches, DBS for obsessive–compulsive disorders, electroconvulsive therapy, etc. and will not be discussed here (Benabid et al., 2005; Weinstein, 2001). Protocols for seizure generation: kindling

Fig. 4. Low frequency stimulation protocols. Different frequencies and several pulse sequences were tested for their ability to elicit robust LTD. Used with permission From Mockett et al. (2002).

Kindling is a model of epilepotogenesis (Gaito, 1976; Goddard, 1967; McIntyre et al., 2002; Mody and MacDonald, 1995; Racine, 1978; Weiss et al., 1995) where the term was first proposed by Goddard and colleagues who performed much of the early work (Goddard, 1967). Epileptogenesis is a set of progressive neurochemical, neuroanatomical, and neurophysiological changes that lead to spontaneous recurrent seizures (Stables et al., 2002). Kindling protocols (Table 2) involve repeated, but intermittent, electrical (or chemical) stimulation that ultimately results in permanent change that is displayed by progressive motor and generalized spontaneous recurrent seizures without the production of tissue damage (Cheng et al., 2002; Kalichman, 1982; McIntyre et al., 2002; Mody and MacDonald, 1995; Racine, 1978; Weiss et al., 1995). In many kindling studies with rats, electrical stimulation (i.e., amygdala) is continued until the animal develops stage-5 convulsive seizures or clonic–tonic– clonic seizures involving all four limbs (Chen et al., 1996; McIntyre et al., 2002). One particularly common protocol utilizes 60 Hz, which was realized when Goddard tried a variety

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Table 2 Representative electrical stimulation protocols for inducing kindling Pulse frequency (pulse type) (Hz)a

Total no. of pulses/pulse duration (ms)

No. of bursts/burst duration (s)

No. of trains/ interval (s)

No. of sessions/ interval (h)b

Intensityc

Hippocampal region stimulated

Reference

40 (Square) 5 (Square) 60 (Square, B) 100 (Square, B) 62.5 (Square, B) 50 (Square, B) 60 (Square, B) 60 (Sinusoidal)

200/25 50/0.2 30/1 50/0.2 62.5/1 (50–100)/0.1 60/NS N/A

1/10 1/10 1/0.5 1/0.5 1/1 1/(1–2) 1/1 1/2

NA NA NA 720/5 NA NA NA NA

1/0 15/24 Variable/24 (<15)/24 50/24 Variable/24 Variable/24 Variable/24

4.5 mA AD AD (<2 mA) 0.2–4 mA 0.75 mA 2–3 mA 1–1.5 mA AD

Ventral Perforant path CA1 Various Various Schaeffer collaterals Granule cells Dorsal

(Bolkvadze et al., 2006) (Bragin et al., 2002) (Valentine et al., 2005) (Alonso-Deflorida and Delgado 1958) (Goddard et al., 1969) (Faas et al., 1996) (Mody and MacDonald, 1995) (McIntyre et al., 2002)

Abbreviations: B = biphasic; NA = not applicable; NS = not specified. a If specified in the study, the letter B is used to signify biphasic stimulation. b When variable is specified, sessions were continued until seizure activity was observed. c The term AD signifies that a stimulation intensity was set at the level necessary to achieve afterdischarge.

of stimulation frequencies (25, 60, and 150 Hz) and found that the animals were maximally sensitive to 60 Hz (Goddard et al., 1969). Other stimulation parameters have also been compared and stimulation intensity does appear to make a difference, but in a specific way. For example, Goddard first showed that varying the intensity had little effect on the number of stimulations required to kindle the amygdala, a region that is involved in linking emotion to memory (Goddard et al., 1969). However, Racine et al. found that intensity made a difference in the sense that epileptiform afterdischarges were required to produce the neural changes underlying the kindling effect (Racine, 1978; Racine, 1972). In this study several weeks of below afterdischarge threshold stimulation did not facilitate subsequent kindling with suprathreshold stimulation. In addition, varying the intensity above threshold (400 vs. 1000 μA) seemed to make little or no difference on kindling rate. Collectively, these studies did show the importance of the afterdischarge in kindling. With regard to intertrial intervals, Goddard et al. (1969) also found that the same number of stimulations were required whether they were spaced by 24 h or 7 days. Finally, most protocols to our knowledge use square wave pulse sequences, although a few have used sinusoidal (Table 2). Common sites for stimulation include the hippocampus and the amygdala; where a number of other sites have also been used with varying responsiveness, but the amygdala appears to be the most sensitive to repeated stimulation (Otani et al., 1989). As a group, protocols involving kindling are primarily used as a model of drug-resistant epilepsy and for the investigation of the developmental aspects of epilepsy (Mody and MacDonald, 1995; Racine, 1978). Is it kindling or plasticity? Interestingly, kindling has been studied not only as a model for epilepsy, but also as a form of long-term neural plasticity since it results in a permanent change in the nervous system (Otani et al., 1989; Weiss et al., 1995). It is likely that kindling protocols trigger a very large number of effects, some of which are presumably still unknown. Some of these effects appear

similar to LTP (and might be a form of LTP), while other effects appear quite different than LTP. Goddard in his initial studies with kindling was actually interested in the effects of electrical stimulation (in the amygdala) on learning performance in rats (Goddard, 1967). Importantly, it should be noted that kindling protocols work best in neural networks that are responsible for learning and memory (McIntyre et al., 2002). Interestingly, the electrical stimulation protocols for kindling are very similar to those used for LTP (i.e., 50 to 100 Hz, for ∼ ≥ 1 s; 50–100 μA or intensity is determined by the level of afterdischarge) (Otani et al., 1989; Weiss et al., 1995). In addition, evidence exists for learning effects that are paralleled by kindling, which include positive transfer from one task to another (or one kindling site to another), negative transfer effects, interference effects, and spontaneous recovery, which are all learning effects with kindling analogs (McIntyre and Goddard, 1973; McIntyre et al., 2002). Finally, clinical studies (Hermann et al., 1981) have shown that epilepsy often impairs learning and memory and that an increase in kindling trials in animals increases subsequent learning disabilities (McIntyre, 1979). Protocols for seizure attenuation As mentioned above, increasing literature suggests that therapeutic electrical stimulation for attenuating seizure activity is in some cases an effective therapy or at least may be a possibility in the future (Benabid et al., 2005). For example, vagal-nerve stimulation has been shown effective and has been used for a number of years and is now licensed in several countries (Theodore and Fisher, 2004). To date, a number of experimental studies have been conducted for attenuating seizure activity in either animals or humans in several target sites (Benabid et al., 2005; Weinstein, 2001). With regard to studies involving the hippocampus, less work has been attempted and with mixed success. To this end, some investigators have used sinusoidal fields (20–50 Hz) (Bikson et al., 2001), whereas others have used square pulse sequences in their attempts to reduce seizure activity (Weiss et al., 1995). In animals studies, Weiss et al. showed that the

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application of 1 Hz for 15 min (100 μs pulse width) to the hippocampus or amygdala following the kindling stimulus (60 Hz for 1 s once daily; 1 ms pulse width) produced a marked and long lasting suppressive effect on seizure activity (Weiss et al., 1995). However, in a follow-up study by the same group, it was reported that the stimulators that were used in the original study emitted an unexpected low level (i.e., 5–15 μA) direct current, which may have had a significant effect on the observed inhibition on seizure activity (Weiss et al., 1995). In human patients previously exposed to antiepileptic drugs (n = 16), Velasco et al. (2000a,b) performed subacute and chronic DBS using electrical stimulation protocols (130 Hz; bipolar; 450 μs pulse duration; amplitude 200–400 μA) for 23 h per day, in the hippocampus of individuals with intractable temporal lobe seizures. They report that subacute stimulation abolished clinical seizures and significantly reduced the number of interictal spikes at focus after 5–6 days. Furthermore, chronic stimulation appeared to persistently block temporal lobe epileptogenesis for 3–4 months with no apparent effects on short-term memory. In another smaller study, DBS was applied to the amygdalo-hippocampal region where 3 patients had at least a 50% reduction in seizure frequency at a 5-month follow up (Vonck et al., 2002). DBS has also been applied to several regions in addition to the hippocampus and includes the cerebellum, caudate nucleus, centromedian thalamus, anterior thalamus, subthalamus, and neocortical seizure foci, however, the best structures to stimulate and the most effective stimulation protocols to use are still unknown (Theodore and Fisher, 2004). In addition, high versus low frequency stimulation protocols have contrasting effects in different regions and in different models and why this is the case is still not clear (Albensi et al., 2004; Theodore and Fisher, 2004). Transcranial magnetic stimulation (TMS), has also been widely used in clinical neurology and has been shown to be simple and non-invasive and if a convenient method is devised for chronic stimulation, this method may hold great promise for the future (Theodore and Fisher, 2004). Discussion and conclusions One critical aspect that needs mentioning is regardless how effective electrical stimulation protocols might be they are all artificial and it is possible that even the most effective protocols trigger a highly synchronous discharge that is unlikely to ever exist in nature. Furthermore, a highly focused pattern of stimulation often times targets only one pathway or a limited number of pathways, which is also not typical. Obviously, the methods that lead to these results serve us well experimentally since we are able to gain control over the relevant variables, but it is still absolutely essential that we recognize that the discharge patterns we observe are probably far from normal. Therefore, caution in general is necessary when discussing stimulation protocols. It should be understood from this review that considerable work has already been accomplished thus showing the effectiveness of some protocols over others for LTP induction. In addition, several key studies have determined that some LTP

protocols (e.g., theta and PB) are more relevant than others since they might more closely simulate normal discharge characteristics of hippocampal neurons. Theta protocols appear to be the most effective and the most relevant. Interestingly, HFS protocols continue to be widely used probably because they are more familiar to a wide range of investigators and also perhaps because they have the potential for comparison with other studies since their use has been so widespread. In vitro studies also indicate that similar to LTP, different temporal forms of LTD can be induced by varying the LFS intensity. However, it is possible that the most effective stimulation frequencies might be the result of optimizing the timing of converging inputs. For example, in LTP experiments other inputs are intentionally bypassed. Moreover, the use of 400 Hz stimulation protocols for in vivo LTP seem to have evolved more as a way to avoid afterdischarges rather than as a way to more accurately simulate CA1 firing. Given its importance, it is surprising that more research on relevant in vivo protocols for LTP has not been conducted to date. Curiously, there does appear to be an intimate connection between the induction of LTP and the induction of epileptiform activity where kindling is in some ways analogous to normal learning and memory or at least might involve similar mechanisms. However, electrical protocols involving kindling have been primarily used as a model of drug-resistant epilepsy. In addition, stimulation protocols for LTP need to be discussed since the LTP discharge patterns should not be assumed to be typical discharge patterns. This is even more relevant for kindling protocols since kindling generates very abnormal discharge patterns, which further complicates our interpretation. It also seems that our understanding of how electrical stimulation leads to various types of biological phenomena is rudimentary and no general theory has been advanced (to date) that accounts for the reported responses to all types of electrical stimulation. To date, one popular model by Bienenstock et al. (1982) has been put forth, which describes a sliding synaptic modification threshold and also theoretically relates LTD to LTP. However, it seems that attempts to develop a general and unified theory of electrical stimulation has been disregarded and the fields involving epilepsy and neuronal excitability have moved forward disconnected from studies involving synaptic plasticity. However, recent studies involving DBS protocols for attenuating neuronal activity might have led to another turning point in this evolution since the advancement of the DBS technique seems dependent on early neurophysiological studies as well as on more recent methods and ideas from bioengineering, neurology, and neurosurgery. To date, protocols involving the attenuation of neuronal firing and even seizure activity are promising, but therapeutic results in just a few studies are equivocal at best (i.e., for epilepsy). In conclusion, the future merging of ideas and of disciplines may shed light on some of the important remaining questions in this fascinating field, which involve the effects of electrical stimulation on living tissue!

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