Long-term plasticity of hippocampal interneurons during in vivo memory processes

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ScienceDirect Long-term plasticity of hippocampal interneurons during in vivo memory processes Karri Lamsa1 and Petrina Lau2

Formation of a cell assembly, a group of cortical neurons that function co-operatively to sustain an active memory trace, arises from changes in the connections between neurons. Establishment of memory traces is thought to rely on long-term plasticity in excitatory glutamatergic synapses interconnecting principal cells. In addition, recent studies in the hippocampus in vivo indicate that reconfiguration of GABAergic inhibitory interneuron activity also occurs during long-term memory encoding. Recent experiments in anesthetized, as well as in freely moving animals, demonstrate that learning-related hippocampal activities are associated with persistent changes in GABAergic interneuron firing rates and alterations in protein expression levels regulating GABA release.

to establish new associations, and disband old ones, to reconfigure the ensembles to represent updated mnemonic information [3,7]. This review gives an overview of learning-related interneuron plasticity in the hippocampus in vivo. Although the causal link between learning and long-term plasticity of inhibitory interneurons is missing, recent studies have reported associations between behavior and the plasticity. Long-term synaptic plasticity of signaling to and from interneurons, explored in slice preparations ex vivo, has been recently reviewed elsewhere [8,9,10].

Addresses 1 Department of Physiology, Anatomy and Neuroscience, University of Szeged, Ko¨ze´p Fasor 52, 6720 Szeged, Hungary 2 MRC Harwell Institute, Harwell Campus, Oxfordshire OX11 0RD, United Kingdom

GABAergic interneuron discharge is an integral part of the mnemonic engram [1,11–13]. It was recently proposed that interneuron activity might appear as ‘inhibitory assemblies’ that correspond as an inhibitory neuron representation to the spatio-temporally patterned firing of pyramidal cells in memory engrams [14,15]. Consequently, like the pyramidal cell firing the configured discharge of hippocampal GABAergic interneurons as a part of the memory representations should also be reorganized by learning experiences. Recently, studies in the hippocampus in vivo demonstrated that learningrelated processes either persistently potentiate or suppress synaptic excitatory communication from pyramidal cells to specific GABAergic inhibitory interneuron types [16,17,18]. In addition, experiments utilizing hippocampal slice preparations have identified various forms of activity-induced interneuron long-term plasticity in the CA1 area interneurons. For instance, many glutamatergic synapses onto parvalbumin-expressing (PV+) interneurons show long-term potentiation (LTP) ex vivo by activation of the group I metabotropic glutamate receptor and the calcium-permeable a-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA)-receptor [19–22], but some afferents exhibit LTP that depends on the glutamate N-methyl-D-aspartate receptor (NMDAR) [23]. The synaptic LTP in PV + basket cells is also associated with a persistently decreased action potential firing threshold for the synaptic excitation [20,24]. In addition, glutamatergic synapses onto the CA1 area ivy cells exhibit lasting potentiation which is independent of glutamate NMDARs [18,25].

Corresponding author: Lamsa, Karri ([email protected])

Current Opinion in Neurobiology 2019, 54:20–27 This review comes from a themed issue on Neurobiology of learning and plasticity Edited by Scott Waddell and Jesper Sjostrom

https://doi.org/10.1016/j.conb.2018.08.006 0959-4388/ã 2018 Elsevier Ltd. All rights reserved.

Introduction Synaptic inhibition provided by firing of GABAergic inhibitory interneurons is crucial for the spatial and temporal organization of hippocampal network activities, and is necessary for the formation of cell assemblies that are thought to represent mnemonic information [1,2,3]. Cell assemblies are dynamic and are reconfigured during learning, such as hippocampal spatial remapping [4–6]. Although the reconfiguration of assemblies is incompletely understood, persistent plasticity of neuronal recruitment is likely to be required to form new assemblies and to suppress obsolete mnemonic engrams that represent less relevant information in a changed environment. Thus in these operations learning-dependent longterm plasticity processes allow an active group of neurons Current Opinion in Neurobiology 2019, 54:20–27

Configured hippocampal interneuron activity as a part of mnemonic processes

Theoretical models propose persistent changes in the synaptic inhibition of principal cells in processes updating mnemonic information [15,26]. Computational simulations indicate that stability of a newly formed pyramidal www.sciencedirect.com

Long-term plasticity of hippocampal interneurons during in vivo memory processes Lamsa and Lau 21

assembly needs ‘inhibitory assembly’ reorganization in parallel, either by changing GABAergic inhibitory synapses to the pyramidal cells or altering excitatory synapse weights to the interneurons [14,27].

Two lines of evidence for interneuron plasticity in vivo Evidence for learning-associated long-term plasticity of hippocampal interneurons in vivo signaling comes from two different experimental settings. First, from experiments entraining synapses with stimulation in anesthetized animals, and second, from studies examining interneurons during behavioral learning of animals (Figure 1). Long-term plasticity of interneuron recruitment by synaptic stimulation

Synaptic LTP, as well as long-term depression (LTD), are experimental phenomena that are widely assumed to Figure 1

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Evidence for learning-related long-term plasticity in hippocampal interneurons comes from two different experimental settings. (a) Experiments entraining synapses with stimulation in anesthetized animals. Recorded (r) CA1 area interneuron firing response to microelectrode stimulation (s) of a glutamatergic projection pathway shows either (i) LTP or (ii) LTD or no change (nc) when compared before (pre) and after (post) a brief train of high-frequency stimulation. (b) Studies examining interneurons during behavioral learning of animals. During hippocampal spatial remapping, multicore microelectrode recording (r) in the CA1 area reveals reconfiguration of pyramidal cell-interneuron monosynaptic spike couples. (i–iii) Pyramidal cells, which are active both in the old and in the new neuronal assemblies (representing old and new spatial maps respectively), and remapped, show either persistent (i) strengthening, or (ii) weakening, or (iii) no change in the spike coupling to the interneuron. In addition, (iv) some pyramidal cells are disbanded from the new neuronal assembly while (v) novel pyramidal cells become spike-coupled to the interneuron. www.sciencedirect.com

relate to learning-driven alterations in the strength of neural connections. They are typically induced by specific synaptic stimulation patterns, either in a brain slice preparation or in the intact brain, substituting for behavioral training [4–6]. Current understanding of the mechanisms of induction and expression of LTP and LTD in hippocampal interneurons mainly comes from results obtained ex vivo [8,9,10], and relatively few studies have been carried out in a living animal. The very first study exploring the topic in vivo was performed by Buzsaki end Eidelberg (1982) in anesthetized rodents [28]. Stimulating the excitatory glutamatergic commissural or the associational hippocampal pathway to the CA1 area, or the commissural or the perforant path to the dentate gyrus, and using extracellular measurement of action potentials in putative interneurons, they found that high-frequency discharge of the fibers (akin to that used in LTP studies in pyramidal cells) led to a persistent increase in the probability of synaptically-evoked action potentials in fast-spiking interneurons. Tomasulo et al. (1996) showed similar LTP in interneurons in the dentate gyrus [29] explaining earlier findings on LTP of disynaptic GABAergic inhibition in this area by glutamatergic fiber high-frequency stimulation [30,31]. Recently, a study from Lau et al. (2017) reproduced these findings in the CA1 area and demonstrated LTP of firing of specialized GABAergic interneuron types identified anatomically [18]. The results were the first to identify hippocampal interneuron types exhibiting long-term plasticity in vivo. The study demonstrated LTP but also LTD-like changes in commissural pathway excitation of the PV + basket cells that provide GABAergic inhibition to the perisomatic region of the CA1 pyramidal cells. In addition, plasticity was observed in PV + bistratified cells, and in neuronal nitric oxide synthase-immunopositive (nNOS+) ivy cells [18], which both inhibit pyramidal cell dendrites [32]. Their work also studied whether different hippocampal brain states, determined by local field potential (LFP) oscillations, played a role in the interneuron plasticity. However, they reported that neither theta (3–6 Hz) nor slow-wave (1–3 Hz) oscillation activity in the CA1 area at the time when high-frequency afferent stimulation was applied, could determine which type of plasticity (the LTP or the LTD) was generated. Thus, the bidirectional modulation of interneuron plasticity is more likely determined by other factors such as the specificity of afferent excitatory synapses, effect of neuromodulatory mechanisms such as activation of monoaminergic or cholinergic fibers during stimulation, or the activity history of the interneurons [23,33,34]. The LTP and LTD in the identified CA1 area PV + basket cells and nNOS + ivy cells in vivo by afferent stimulation is illustrated in Figure 2. Current Opinion in Neurobiology 2019, 54:20–27

22 Neurobiology of learning and plasticity

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Long-term plasticity of synaptic excitation of identified CA1 area interneurons by glutamatergic fiber stimulation in the anesthetized rat. (a) LTP and LTD of synaptically-evoked spiking in CA1 area ivy cells. (a1) Spike distribution (‘synaptic’, black dots) in an ivy cell before and after highfrequency commissural pathway stimulation (dotted line). Blue dots show failures to evoke a spike by synaptic stimulation. Spontaneous spikes during the experiment are shown in the histogram on the left. (a2) Top: Superimposed traces show evoked spikes and failures at the two time points. Bottom: Histogram summarizing the increase in synaptically-evoked firing probability. (a3) Illustration of nNOS + ivy cell showing LTP (NB indicates visualized neurobiotin marker in the cell). (a4) Spike probability (red, scaling on left) in two ivy cells one showing LTP (top) and another LTD (bottom). Black symbols show spontaneous firing. (b) LTP and LTD in PV + basket cells (PV + BC). (b1) PV + BC with LTD (axon characteristically immunonegative for cannabinoid receptor type 1). (b2) One PV + BC with LTP (top) and another showing LTD (bottom). (c) The hippocampal brain state or the interneuron’s spontaneous firing level do not explain the bidirectional plasticity. (c1) Comparison of the spontaneous firing rate (Hz) and the evoked spike long-term plasticity (baseline-normalized). Fast-spiking cell types are annotated and shown in different colors as indicated. (c2) Relationship of the CA1 area LFP activity pattern and long-term plasticity. The LFP index 0 indicates equal average power in LFP slow-wave (1–3 Hz) and theta (3–6 Hz), ‘SW’ and ‘theta’ represent 1–3 Hz and 3–6 Hz activity only. Modified with permission from Lau et al. (2017) and Brain Structure and Function [18].

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Long-term plasticity of hippocampal interneurons during in vivo memory processes Lamsa and Lau 23

Reconfiguration of interneuron firing during behavioral learning

While the in vivo studies above reported plasticity in hippocampal interneurons using electrical stimulation of the excitatory pyramidal cell axons, a study by Dupret et al. (2013) approached the topic from another angle [17]. They tested how natural behavior-driven pyramidal cell-to-interneuron communication in the hippocampus is altered during monitored learning. They trained rats (with multicore microelectrodes positioned in the hippocampus) to perform goal-oriented spatial learning tasks to memorize new locations of food rewards daily, in an otherwise familiar environment. Remembering altered reward locations required an update of the hippocampus-based memory for the goal locations. Meanwhile, they monitored activity of interneurons and pyramidal cells in the CA1 area. Temporally-coupled pyramidal cell and interneuron firing (spikes distinguished by the different waveforms) consistently occurred during spatial exploration with hippocampal assemblies. Sharply time-locked spikes with interneurons following pyramidal cells firing at short delays represented monosynaptically connected pairs [17,35]. They showed that the firing of CA1 area pyramidal cell-tointerneuron monosynaptically connected pairs was reorganized during goal-oriented learning (Figure 3). New pyramidal cell assemblies appeared in the hippocampal LFP theta oscillation (4–8 Hz) cycles as part of neural representation of the hippocampus-based spatial map, and the interneuron spikes developed a novel relationship to the pyramidal cell spikes. First, some interneurons became associated with new pyramidal cell assemblies, while old assembly pyramidal cells were uncoupled from them. Second, pyramidal cells which were active both in the old and the new spatial maps and remapped their place field, strengthened their firing coupling to some interneurons, while their coupling to others diminished. The more often the pyramidal cell fired with an interneuron during the behavioral training, the larger was the change in their coupling strength at the end. These persistent changes were also seen in hippocampal theta oscillation network activity occurring during sleep after the behavioral learning was completed. Furthermore, the changes similarly occurred in the memory recall session after that sleep. Altogether, their results show that hippocampal learning is associated with persistent changes in monosynaptic pyramidal cell-to-interneuron coupling in the CA1 area. These altered firing associations could at least partly be explained by LTP and LTD in the synaptic excitation of interneurons described above [18]. Therefore, a recent study by Zarnadze et al. (2016) is interesting proposing that short hippocampal gamma frequency network activity episodes, driven by specific states during learning in vivo, permanently potentiate excitatory synaptic input to the hippocampal PV + fastspiking interneurons [16]. The observed interneuron www.sciencedirect.com

LTP required the group I metabotropic glutamate receptor, which has also been demonstrated critical for LTP in many interneurons ex vivo [19,22,36]. The interneuron LTP was also associated with increased GABAergic inhibition of local pyramidal cells. The study showed that the LTP in glutamatergic excitation of PV + interneurons was cell type-specific, since it was not observed in GABAergic basket cells expressing the marker protein cholecystokinin (but not PV). The results indicate that learningassociated hippocampal network activity states, such as gamma oscillations, generate LTP in PV + basket cells.

Learning-driven plasticity in mechanisms regulating GABA release from interneurons

Interestingly, another type of learning-associated lasting plasticity in the interneurons (not directly showing changes in their discharge but modulating inhibitory GABAergic synapses to pyramidal cells) has been characterized in the hippocampus. Basket cells in the CA1–CA3 area show changes in the expression level of the calciumbuffering protein parvalbumin and the GABA-synthetizing enzyme glutamate acid decarboxylase isoform 67 (GAD67) by hippocampal learning [37]. Spatial learning experiments in the Morris water maze have revealed that PV and GAD67 levels in basket cells are low during initial training days in mice exploring in an altered environment. This is followed by a shift to their high expression levels, which reaches a peak after the learning completion. Thus, the hippocampal CA1 area basket cells switch their PV and glutamate acid decarboxylase expression configuration depending on whether the learning involves acquisition of new information or consolidation of the memories [38,39]. The plasticity of PV + basket cells involving changes in PV and GAD67 expression levels after memory acquisition was required for normal learning in spatial navigation tasks. The plasticity required activation of dopamine D1/5 receptors and cyclic AMP (cAMP) signaling in PV + neurons [40]. The dependence of the process on interneuronal cAMP-signaling in vivo is interesting, because studies ex vivo have shown dependence of a 24-hour LTP in interneurons on the cAMP response element-binding protein (CREB) [41]. Activated CREB results in production of the intracellular second messenger cAMP. The findings on the interneuron PV and GAD67 levels controlled by learning are exciting, since PV is a calcium buffer regulating GABA transmitter release from the basket cell synapses [42]. Correspondingly, the altered GAD67 expression level and the consequently changed GABA-synthesis in basket cells is likely to modify the strength of GABAergic inhibitory synapses to pyramidal cells [43,44]. However, further studies will be needed to understand how these learning-regulated basket cell states contribute to the functional plasticity of pyramidal cell-interneuron couples in the hippocampal assemblies. Current Opinion in Neurobiology 2019, 54:20–27

24 Neurobiology of learning and plasticity

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Interneuron firing associations to CA1 pyramidal cells change persistently during goal-oriented spatial learning. (a) Permanent change in spike coupling of some CA1 interneurons to the pyramidal cells by expression of new pyramidal cell assemblies after changing a goal reward location in an otherwise familiar spatial environment. (a1) Firing of three interneurons (red, blue and grey lines) during flickering expression of the new and the old pyramidal cell assemblies at the early stage of learning (interneuron firing score indicates a rate change over the mean rate). Positive histogram index (PCAE) indicates that new assemblies predominate at the time point whereas in a negative index the old map assembly is stronger. Blue line interneuron increases its firing rate in the new assemblies, whereas the red interneuron decreases it, and the grey shows no alteration in the discharge. (a2-4) The firing association of the three CA1 interneuron categories to the old and the new pyramidal cell assemblies. Individual interneurons (different colors) gradually (a2) increased, (a3) decreased and some (a4) did not change their firing rate coupling to the emerging new pyramidal cell assemblies during learning. (b) and (c) Learning-driven permanently changed monosynaptic pyramidal cell-to-interneuron spike coupling in reconfigured pyramidal assemblies representing the new spatial map. (b1) Cross-correlogram of a monosynaptic firing couple shows increased coupling probability after the learning task (post-probe). (b2) The increased coupling strength also shortens the spike coupling latency. (c1) Another monosynaptic couple developing reduced coupling probability. The weakened (c2) coupling is associated with elongation in the spike coupling latency. (Same couple is shown in four multicore electrode channels 1–4). Firing delay of the interneuron (int.) is 3–5 ms. Int. = interneuron, PC = pyramidal cell. (d) Some pyramidal cells active in the old and the new map, and remapped, are coupled to same individual interneuron. (d1) Pyramidal cells (Pyr 1 and 2) are both active before and after learning the new goals. Colored dots show discharge locations of the pyr1 and 2 on the map. (d2) Pyr1 coupling to the interneuron is strengthened in a new spatial representation. Pyr 2 coupling is suppressed. Images were modified with permission from Dupret et al. (2013) and Neuron [17].

Logical operations of interneuron plasticity in hippocampal cell assemblies In a recent review, MacKenzie (2017) summarizes how persistent learning-related changes in different CA1 interneuron types may tune the pyramidal cell contribution to cell assemblies [15]. Basically, changes in the Current Opinion in Neurobiology 2019, 54:20–27

firing rates of interneurons targeting the soma of pyramidal cells (such as basket cells) largely determine their action potential output. Plasticity in the firing behavior of these inhibitory interneurons is able to control which pyramidal cells fire and the timing of their discharges in the hippocampal ensembles. Correspondingly, www.sciencedirect.com

Long-term plasticity of hippocampal interneurons during in vivo memory processes Lamsa and Lau 25

GABAergic interneurons that innervate pyramidal cell dendrites (such as bistratified and ivy cells) control the integration of excitatory synaptic inputs from afferent areas, including the entorhinal cortex, CA3 and CA1. Plasticity in the firing rate of these interneurons can determine which afferent excitatory neurons efficiently contribute to the pyramidal cell excitation that eventually triggers its firing [45,46], thus defining the so called receptive field of the individual CA1 pyramidal cell. We have listed below three possible ways how the LTP and LTD in the pyramidal cell-to-interneuron connections could contribute to the hippocampal pyramidal cell assembly reconfiguration. LTP in a pyramidal cell-to-interneuron connection reorganizes the inhibitory assembly and suppresses the old assembly of pyramidal cells

the CA1 area. Hence, small interfering RNA (siRNA) or short hairpin RNA (shRNA)-mediated suppression of metabotropic glutamate receptor type 1 (mGluR1) or type 5 (mGluR5) [19,36], T-type calcium channels [48], or cAMP response element-binding protein (CREB) [41] in the hippocampal PV + interneurons could give important information on how interneuron plasticity contributes to the behavioral learning and re-organization of the CA1 area cell assemblies. Correspondingly, controldopamine/cAMP-regulated phosphoprotein ling (DARPP-32), or neuronal extracellular signal-regulated kinase (ERK) [40], in basket cells, could reveal how learning-regulated PV and GAD67 levels in turn contribute to the functional plasticity of pyramidal cell-interneuron couples in the hippocampal assemblies.

The formation of a new active pyramidal cell-interneuron spiking couple allows reconfiguration of the GABAergic inhibitory assembly. The new pyramidal cell influencing interneuron firing will readjust the inhibitory neuron representation to the patterned pyramidal cell firing by altering the timing of the synaptic inhibition in other pyramidal cells. This can suppress pyramidal cells that represent old assemblies with obsolete information [17].

In addition to the CA1 area, activity-induced long-term plasticity of PV + basket cells occurs in other hippocampal fields including the CA3 area and dentate gyrus [16,19,37]. Early studies in anesthetized animals have shown that high-frequency glutamatergic fiber activity elicits LTP in many interneurons in these regions [28– 31]. Akin to the CA1 area, interneuron plasticity may be involved in hippocampus-dependent learning in the CA3 area and dentate gyrus.

LTD in pyramidal cell-to-interneuron contact disbands the old ensemble

Conflict of interest statement

Correspondingly, LTD in monosynaptic pyramidal cellto-interneuron connections directly destabilizes the old assembly-associated GABAergic inhibition. Such process may be involved in the remapping of the hippocampal spatial memory representations [47].

Acknowledgements

LTD in disbanding old ensembles releases inhibition in the new pyramidal cell ensembles

Suppression of disynaptic inhibition, caused by LTD in the old assembly pyramidal cell-to-interneuron contacts, helps new pyramidal cells to form novel ensemble activity to jointly represent information. The formation of new CA1 pyramidal cell assemblies benefits from the LTD, since this releases them from the disynaptic inhibition generated by the old assembly pyramidal cells [47].

Future directions Recent technological inventions enable new experimental approaches, which were nearly unimaginable at the time when the first studies reporting the plasticity of inhibition in vivo were performed. At present, targeted and cell type-specific expression of gene products, such as gene silencers, provides a highly specific tool to test a role of selected key molecules (suppressing their expression levels in interneurons by RNA interference) in the plasticity in vivo, and to study in parallel, possible behavioral changes in hippocampus-dependent learning. Studies ex vivo during the past decades have identified key signaling molecules crucial for LTP and LTD in interneurons of www.sciencedirect.com

Nothing declared.

We thank Jozsef Csicsvari and Dimitri M. Kullmann for their comments on the manuscript and Hilary Gates for language check. This work was supported by the Hungarian Academy of Sciences Neuroscience Program 2017-1.2.1-NKP-2017-00002 (to K.L.).

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