Connections In CA3 Research Articles

Impaired synaptic plasticity in an animal model of autism exhibiting early hippocampal GABAergic-BDNF/TrkB signaling alterations

In Neurodevelopmental Disorders, alterations of synaptic plasticity may trigger structural changes in neuronal circuits involved in cognitive functions. This hypothesis was tested in mice carrying the human R451C mutation of Nlgn3 gene (NLG3R451C KI), found in some families with autistic children. To this aim, the spike time dependent plasticity (STDP) protocol was applied to immature GABAergic Mossy Fibers (MF)-CA3 connections in hippocampal slices from NLG3R451C KI mice. These animals failed to exhibit STD-LTP, an effect that persisted in adulthood when these synapses became glutamatergic. Similar results were obtained in mice lacking the Nlgn3 gene (NLG3 KO mice), suggesting a loss of function. The loss of STD-LTP was associated with a premature shift of GABA from the depolarizing to the hyperpolarizing direction, a reduced BDNF availability and TrkB phosphorylation at potentiated synapses. These effects may constitute a general mechanism underlying cognitive deficits in those forms of Autism caused by synaptic dysfunctions.

The Functional Plausibility of Topologically Extended Models of RBMs as Hippocampal Models

The hippocampus has distinctive functional and structural properties. In this research, we utilize Restricted Boltzmann Machines (RBMs) based models inspired by distinctive structures found in hippocampus; neurogenesis in the dentate gyrus (DG) and recurrent connections in CA3. We review two types of topologically extended models of RBMs inspired by hippocampus. In one type of models, units are dynamically added during the training phase, and in the other type, connections are partly recursive. We analyzed these models both as separate models and combined model. The two types of the proposed models implement functions that the hippocampus has but the classical RBMs don’t. Furthermore, by combining the two proposed models, memorization of chronologically ordered data and memory reconstruction tasks’ performance improved significantly.

Control of Spike Transfer at Hippocampal Mossy Fiber Synapses In Vivo by GABAA and GABAB Receptor-Mediated Inhibition.

Activity-dependent changes in synaptic strength constitute a basic mechanism for memory. Synapses from the dentate gyrus (DG) to the CA3 area of the hippocampus are distinctive for their prominent short-term plasticity, as studied in slices. Plasticity of DG-CA3 connections may assist in the encoding of precise memory in the CA3 network. Here we characterize DG-CA3 synaptic transmission in vivo using targeted optogenetic activation of DG granule cells while recording in whole-cell patch-clamp and juxtacellular configuration from CA3 pyramidal cells and interneurons. We show that, in vivo, short-term plasticity of excitatory inputs to CA3 pyramidal cells combines with robust feedforward inhibition mediated by both GABAA and GABAB receptors to control the efficacy and temporal rules for information transfer at DG-CA3 connections.

Pattern separation, completion, and categorisation in the hippocampus and neocortex

The mechanisms for pattern completion and pattern separation are described in the context of a theory of hippocampal function in which the hippocampal CA3 system operates as a single attractor or autoassociation network to enable rapid, one-trial, associations between any spatial location (place in rodents, or spatial view in primates) and an object or reward, and to provide for completion of the whole memory during recall from any part. The factors important in the pattern completion in CA3 and also a large number of independent memories stored in CA3 include: a sparse distributed representation, representations that are independent due to the randomizing effect of the mossy fibres, heterosynaptic long-term depression as well as long-term potentiation in the recurrent collateral synapses, and diluted connectivity to minimize the number of multiple synapses between any pair of CA3 neurons which otherwise distort the basins of attraction. Recall of information from CA3 is implemented by the entorhinal cortex perforant path synapses to CA3 cells, which in acting as a pattern associator allow some pattern generalization. Pattern separation is performed in the dentate granule cells using competitive learning to convert grid-like entorhinal cortex firing to place-like fields, and in the dentate to CA3 connections that have diluted connectivity. Recall to the neocortex is achieved by a reverse hierarchical series of pattern association networks implemented by the hippocampo-cortical backprojections, each one of which performs some pattern generalization, to retrieve a complete pattern of cortical firing in higher-order cortical areas. New results on competitive networks show which factors contribute to their ability to perform pattern separation, pattern clustering, and pattern categorisation, and how these apply in different hippocampal and neocortical systems.

Diurnal inhibition of NMDA-EPSCs at rat hippocampal mossy fibre synapses through orexin-2 receptors.

Diurnal release of the orexin neuropeptides orexin-A (Ox-A, hypocretin-1) and orexin-B (Ox-B, hypocretin-2) stabilises arousal, regulates energy homeostasis and contributes to cognition and learning. However, whether cellular correlates of brain plasticity are regulated through orexins, and whether they do so in a time-of-day-dependent manner, has never been assessed. Immunohistochemically we found sparse but widespread innervation of hippocampal subfields through Ox-A- and Ox-B-containing fibres in young adult rats. The actions of Ox-A were studied on NMDA receptor (NMDAR)-mediated excitatory synaptic transmission in acute hippocampal slices prepared around the trough (Zeitgeber time (ZT) 4-8, corresponding to 4-8 h into the resting phase) and peak (ZT 23) of intracerebroventricular orexin levels. At ZT 4-8, exogenous Ox-A (100 nm in bath) inhibited NMDA receptor-mediated excitatory postsynaptic currents (NMDA-EPSCs) at mossy fibre (MF)-CA3 (to 55.6 ± 6.8% of control, P = 0.0003) and at Schaffer collateral-CA1 synapses (70.8 ± 6.3%, P = 0.013), whereas it remained ineffective at non-MF excitatory synapses in CA3. Ox-A actions were mediated postsynaptically and blocked by the orexin-2 receptor (OX2R) antagonist JNJ10397049 (1 μm), but not by orexin-1 receptor inhibition (SB334867, 1 μm) or by adrenergic and cholinergic antagonists. At ZT 23, inhibitory effects of exogenous Ox-A were absent (97.6 ± 2.9%, P = 0.42), but reinstated (87.2 ± 3.3%, P = 0.002) when endogenous orexin signalling was attenuated for 5 h through i.p. injections of almorexant (100 mg kg(-1)), a dual orexin receptor antagonist. In conclusion, endogenous orexins modulate hippocampal NMDAR function in a time-of-day-dependent manner, suggesting that they may influence cellular plasticity and consequent variations in memory performance across the sleep-wake cycle.

Intrinsic mechanisms stabilize encoding and retrieval circuits differentially in a hippocampal network model.

Acetylcholine regulates memory encoding and retrieval by inducing the hippocampus to switch between pattern separation and pattern completion modes. However, both processes can introduce significant variations in the level of network activity and potentially cause a seizure-like spread of excitation. Thus, mechanisms that keep network excitation within certain bounds are necessary to prevent such instability. We developed a biologically realistic computational model of the hippocampus to investigate potential intrinsic mechanisms that might stabilize the network dynamics during encoding and retrieval. The model was developed by matching experimental data, including neuronal behavior, synaptic current dynamics, network spatial connectivity patterns, and short-term synaptic plasticity. Furthermore, it was constrained to perform pattern completion and separation under the effects of acetylcholine. The model was then used to investigate the role of short-term synaptic depression at the recurrent synapses in CA3, and inhibition by basket cell (BC) interneurons and oriens lacunosum-moleculare (OLM) interneurons in stabilizing these processes. Results showed that when CA3 was considered in isolation, inhibition solely by BCs was not sufficient to control instability. However, both inhibition by OLM cells and short-term depression at the recurrent CA3 connections stabilized the network activity. In the larger network including the dentate gyrus, the model suggested that OLM inhibition could control the network during high cholinergic levels while depressing synapses at the recurrent CA3 connections were important during low cholinergic states. Our results demonstrate that short-term plasticity is a critical property of the network that enhances its robustness. Furthermore, simulations suggested that the low and high cholinergic states can each produce runaway excitation through unique mechanisms and different pathologies. Future studies aimed at elucidating the circuit mechanisms of epilepsy could benefit from considering the two modulatory states separately.

Recurrent synapses and circuits in the CA3 region of the hippocampus: an associative network

In the CA3 region of the hippocampus, pyramidal cells excite other pyramidal cells and interneurons. The axons of CA3 pyramidal cells spread throughout most of the region to form an associative network. These connections were first drawn by Cajal and Lorente de No. Their physiological properties were explored to understand epileptiform discharges generated in the region. Synapses between pairs of pyramidal cells involve one or few release sites and are weaker than connections made by mossy fibers on CA3 pyramidal cells. Synapses with interneurons are rather effective, as needed to control unchecked excitation. We examine contributions of recurrent synapses to epileptiform synchrony, to the genesis of sharp waves in the CA3 region and to population oscillations at theta and gamma frequencies. Recurrent connections in CA3, as other associative cortices, have a lower connectivity spread over a larger area than in primary sensory cortices. This sparse, but wide-ranging connectivity serves the functions of an associative network, including acquisition of neuronal representations as activity in groups of CA3 cells and completion involving the recall from partial cues of these ensemble firing patterns.

Persistent firing supported by an intrinsic cellular mechanism in hippocampal CA3 pyramidal cells

Short-term information retention is crucial for information processing in the brain. It has long been suggested that the hippocampal CA3 region is able to support short-term information retention through persistent neural firing. Theoretical studies have shown that this persistent firing can be supported by abundant excitatory recurrent connections in CA3. However, it remains unclear whether individual cells can support persistent firing. In this study, using in vitro whole-cell patch-clamp recordings in a rat hippocampal slice preparation, we show that hippocampal CA3 pyramidal cells support persistent firing under perfusion of the cholinergic agonist carbachol (10 μm). Furthermore, in contrast to earlier theoretical studies, this persistent firing is independent of ionotropic glutamatergic synaptic transmission and is supported by the calcium-activated non-selective cationic current. Because cholinergic receptor activation is crucial for short-term memory tasks, persistent firing in individual cells may support short-term information retention in the hippocampal CA3 region.

The spatial representations acquired in CA3 by self-organizing recurrent connections

Neural computation models have hypothesized that the dentate gyrus (DG) drives the storage in the CA3 network of new memories including, e.g., in rodents, spatial memories. Can recurrent CA3 connections self-organize, during storage, and form what have been called continuous attractors, or charts—so that they express spatial information later, when aside from a partial cue the information may not be available in the inputs? We use a simplified mathematical network model to contrast the properties of spatial representations self-organized through simulated Hebbian plasticity with those of charts pre-wired in the synaptic matrix, a control case closer to the ideal notion of continuous attractors. Both models form granular quasi-attractors, characterized by drift, which approach continuous ones only in the limit of an infinitely large network. The two models are comparable in terms of precision, but not of accuracy: with self-organized connections, the metric of space remains distorted, ill-adequate for accurate path integration, even when scaled up to the real hippocampus. While prolonged self-organization makes charts somewhat more informative about position in the environment, some positional information is surprisingly present also about environments never learned, borrowed, as it were, from unrelated charts. In contrast, context discrimination decreases with more learning, as different charts tend to collapse onto each other. These observations challenge the feasibility of the idealized CA3 continuous chart concept, and are consistent with a CA3 specialization for episodic memory rather than path integration.

The race to learn: Spike timing and STDP can coordinate learning and recall in CA3

The CA3 region of the hippocampus has long been proposed as an autoassociative network performing pattern completion on known inputs. The dentate gyrus (DG) region is often proposed as a network performing the complementary function of pattern separation. Neural models of pattern completion and separation generally designate explicit learning phases to encode new information and assume an ideal fixed threshold at which to stop learning new patterns and begin recalling known patterns. Memory systems are significantly more complex in practice, with the degree of memory recall depending on context-specific goals. Here, we present our spike-timing separation and completion (STSC) model of the entorhinal cortex (EC), DG, and CA3 network, ascribing to each region a role similar to that in existing models but adding a temporal dimension by using a spiking neural network. Simulation results demonstrate that (a) spike-timing dependent plasticity in the EC-CA3 synapses provides a pattern completion ability without recurrent CA3 connections, (b) the race between activation of CA3 cells via EC-CA3 synapses and activation of the same cells via DG-CA3 synapses distinguishes novel from known inputs, and (c) modulation of the EC-CA3 synapses adjusts the learned versus test input similarity required to evoke a direct CA3 response prior to any DG activity, thereby adjusting the pattern completion threshold. These mechanisms suggest that spike timing can arbitrate between learning and recall based on the novelty of each individual input, ensuring control of the learn-recall decision resides in the same subsystem as the learned memories themselves. The proposed modulatory signal does not override this decision but biases the system toward either learning or recall. The model provides an explanation for empirical observations that a reduction in novelty produces a corresponding reduction in the latency of responses in CA3 and CA1.

GABA-mediated membrane oscillations as coincidence detectors for enhancing synaptic efficacy in the developing hippocampus

Spontaneously occurring neuronal oscillations constitute a hallmark of developmental networks. They have been observed in the retina, neocortex, hippocampus, thalamus and spinal cord. In the immature hippocampus the so-called ‘giant depolarizing potentials’ (GDPs) are network-driven membrane oscillations characterized by recurrent membrane depolarization with superimposed fast action potentials. Usually, they last hundreds of ms and are separated by intervals of several seconds. GDPs depend on the synergistic action of GABA and glutamate acting on GABAA and (RS)-a-amino-3-hydroxy-5-methyl-4-isoxadepropionate (AMPA) receptors, respectively. Early in postnatal life, GABA depolarizes and excites the postsynaptic cells due to high intracellular [Cl-] which results mainly from the unbalance of two Cl- co-transporter systems, the NKCCl and KCC2 that enhance and lower intracellular [Cl-], respectively. In accord with the Hebb postulate on activity-dependent synaptic strengthening, here the hypothesis has been tested that GDPs may act as coincident detector signals between pre and postsynaptic activity. This assumption has been verified at poorly developed mossy fiber (MF)-CA3 connections. These synapses are particularly interesting because they can release GABA in addition to glutamate. We found that during the first postnatal week correlated pre (MF) and postsynaptic (GDPs) activity persistently enhances synaptic strength at MF-CA3 connections. This effect was usually restricted to the activated synapse. When the interval between GDPs and MF stimulation was increased, the potentiating effect progressively declined and disappeared. The potentiation depended on the activation of voltage-dependent calcium channels and calcium flux. Moreover, it was clear from our experiments that at this developmental stage GABA is the main neurotransmitter released from the MF. This is consistent with the sequential expression of functional GABA and glutamatergic synapses found in the hippocampus at early developmental stages. Synchronous membrane oscillations may therefore contribute to the refinement of neuronal connectivity before the establishment of the adult neuronal circuit. Later in development when the degree of functional connections is sufficiently high, GDPs would be replaced by more subtle types of signal synchronization such as theta or gamma activity characteristic of the adult network.

Memory retrieval time and memory capacity of the CA3 network: Role of gamma frequency oscillations

The existence of recurrent synaptic connections in CA3 led to the hypothesis that CA3 is an autoassociative network similar to the Hopfield networks studied by theorists. CA3 undergoes gamma frequency periodic inhibition that prevents a persistent attractor state. This argues against the analogy to Hopfield nets, in which an attractor state can be used for working memory. However, we show that such periodic inhibition allows one cycle of recurrent excitatory activity and that this is sufficient for memory retrieval (within milliseconds). Thus, gamma oscillations are compatible with a long-term autoassociative memory function for CA3. A second goal of our work was to evaluate previous methods for estimating the memory capacity (P) of CA3. We confirm the equation, P = c/a(2), where c is the probability that any two cells are recurrently connected and a is the fraction of cells representing a memory item. In applying this to CA3, we focus on CA3a, the subregion where recurrent connections are most numerous (c = 0.2) and approximate randomness. We estimate that a memory item is represented by approximately 225 of the 70,000 neurons in CA3a (a = 0.003) and that approximately 20,000 memory items can be stored. Our general conclusion is that the physiological and anatomical findings of CA3a are consistent with an autoassociative function. The nature of the information that is associated in CA3a is discussed. We also discuss how the autoassociative properties of CA3 and the heteroassociative properties of dentate synapses (linking sequential memories) form an integrated system for the storage and recall of item sequences. The recall process generates the phase precession in dentate, CA3, and entorhinal cortex.

An attractor network in the hippocampus: Theory and neurophysiology

A quantitative computational theory of the operation of the CA3 system as an attractor or autoassociation network is described. Based on the proposal that CA3-CA3 autoassociative networks are important for episodic or event memory in which space is a component (place in rodents and spatial view in primates), it has been shown behaviorally that the CA3 supports spatial rapid one-trial learning and learning of arbitrary associations and pattern completion where space is a component. Consistent with the theory, single neurons in the primate CA3 respond to combinations of spatial view and object, and spatial view and reward. Furthermore, single CA3 neurons reflect the recall of a place from an object in a one-trial object-place event memory task. CA3 neurons also reflect in their firing a memory of spatial view that is retained and updated by idiothetic information to implement path integration when the spatial view is obscured. Based on the computational proposal that the dentate gyrus produces sparse representations by competitive learning and via the mossy fiber pathway forces new representations on the CA3 during learning (encoding), it has been shown behaviorally that the dentate gyrus supports spatial pattern separation during learning, and that the mossy fiber system to CA3 connections are involved in learning but not in recall. The perforant path input to CA3 is quantitatively appropriate to provide the cue for recall in CA3. The concept that the CA1 recodes information from CA3 and sets up associatively learned back-projections to neocortex to allow subsequent retrieval of information to neocortex provides a quantitative account of the large number of hippocampo-neocortical back-projections.

GABA-mediated giant depolarizing potentials as coincidence detectors for enhancing synaptic efficacy in the developing hippocampus.

Spontaneously occurring neuronal oscillations constitute a hallmark of developmental networks. They have been observed in the retina, neocortex, hippocampus, thalamus, and spinal cord. In the immature hippocampus, the so-called "giant depolarizing potentials" (GDPs) are network-driven synaptic events generated by gamma-aminobutyric acid (GABA), which at this stage is depolarizing and excitatory. We have tested the hypothesis that during the first postnatal week, GDP-associated calcium signals may alter the properties of synaptic transmission at poorly developed mossy fiber (MF)-CA3 connections. We found that "pairing" GDPs with MF stimulation induced a persistent increase in synaptic efficacy at MF-CA3 synapses. When the interval between GDPs and MF stimulation was increased, the potentiating effect progressively declined and disappeared. The potentiation depended on activation of voltage-dependent calcium channels and calcium flux. This activity may contribute to the refinement of neuronal connectivity before the establishment of the adult neuronal circuit.

An Id-like current that is downregulated by Ca2+ modulates information coding at CA3-CA3 synapses in the rat hippocampus

Voltage-gated K+ channels localised on presynaptic nerve terminals control information coding by modulating presynaptic firing and synaptic efficacy in target neurones. We found that at CA3–CA3 connections in hippocampal slice cultures, a fast-activating, slowly inactivating K+ conductance similar to the so-called delay current (ID) is responsible for the delayed appearance of the first spike upon membrane depolarisation, for action potential repolarisation and for modulation of transmitter release. The Id-like current was downregulated by intracellular Ca2+, as indicated by the increased delay in the appearance of the first action potential following either the block of Ca2+ flux through voltage-dependent Ca2+ channels with Cd2+ or replacement of the bathing solution with one devoid of Ca2+. In both cases, this effect was reversed by blocking this conductance with a low concentration of 4-aminopyridine (4-AP, 10-50 μM). Application of 4-AP shortened the delay to the first spike generation, prevented the effect of Cd2+ and increased the spike duration. The earlier appearance of the first action potential was also observed in the presence of dendrotoxin-1 (100 nM). In voltage-clamp experiments larger currents were recorded in the absence of extracellular Ca2+, thus confirming the downregulation of the Id-like current by Ca2+ due to the positive shift of its inactivation. Spike broadening was associated with an enhancement of synaptic efficacy in target neurones, as assessed by the increase in EPSC amplitude and in the percentage of successes. Moreover, in the presence of 4-AP, EPSCs appeared with a longer latency and were more scattered. This conductance is therefore crucial for setting the timing and strength of synaptic transmission at CA3–CA3 connections. It is conceivable that switching off ID by increasing intracellular Ca2+ following activity-dependent processes may facilitate network synchronisation and crosstalk between CA3 pyramidal cells, leading to seizure activity.

Heterogeneity of Synaptic Plasticity at Unitary CA3–CA1 and CA3–CA3 Connections in Rat Hippocampal Slice Cultures

Long-term potentiation (LTP) of unitary EPSPs, generated by pairs of monosynaptically connected CA3 and CA1 pyramidal cells, was compared with LTP of extracellularly evoked, multi-unitary EPSPs in rat hippocampal slice cultures. LTP was induced by repeated, synchronous pairing of low-frequency presynaptic and postsynaptic activity. Three differences were observed. First, LTP of multi-unitary EPSPs displayed two phases: transient (<5 min) and sustained. Potentiation of unitary EPSPs displayed both phases in 42% of experiments; the remainder showed sustained potentiation only. Unitary EPSPs displaying transient-sustained and only sustained potentiation could be recorded from single postsynaptic cells, indicating that excitatory synapses on a given cell are heterogeneous with respect to short-term plasticity. Second, whereas LTP of multi-unitary EPSPs never resulted in greater than twofold increases in amplitude (mean potentiation of 175% of control), maximal LTP of unitary EPSPs was as great as 13-fold (mean potentiation of 250%). Third, LTP could not be induced in 24% of unitary EPSPs. We provide here the first evidence for the coexistence of potentiatable and nonpotentiatable synapses on individual postsynaptic neurons. Thirty-seven percent of connections not displaying LTP exhibited long-term depression (LTD), suggesting that the connections were already maximally potentiated. In the remaining 63% of these pairs, neither LTP nor LTD could be induced, despite the existence of a pharmacologically identified, NMDA receptor-mediated EPSP component. In conclusion, there is considerable heterogeneity in the amplitude and time course of LTP expression at different synaptic connections. A substantial proportion of apparently nonplastic synapses probably accounts for the weaker potentiation displayed by compound EPSPs.