Retrieval of contextual memory can be predicted by CA3 remapping and is differentially influenced by NMDAR activity in rat hippocampus subregions.

Episodic memory is essential to navigate in a changing environment by recalling past events, creating new memories, and updating stored information from experience. Although the mechanisms for acquisition and consolidation have been profoundly studied, much less is known about memory retrieval. Hippocampal spatial representations are key for retrieval of contextually guided episodic memories. Indeed, hippocampal place cells exhibit stable location-specific activity which is thought to support contextual memory, but can also undergo remapping in response to environmental changes. It is unclear if remapping is directly related to the expression of different episodic memories. Here, using an incidental memory recognition task in rats, we showed that retrieval of a contextually guided memory is reflected by the levels of CA3 remapping, demonstrating a clear link between external cues, hippocampal remapping, and episodic memory retrieval that guides behavior. Furthermore, we describe NMDARs as key players in regulating the balance between retrieval and memory differentiation processes by controlling the reactivation of specific memory traces. While an increase in CA3 NMDAR activity boosts memory retrieval, dentate gyrus NMDAR activity enhances memory differentiation. Our results contribute to understanding how the hippocampal circuit sustains a flexible balance between memory formation and retrieval depending on the environmental cues and the internal representations of the individual. They also provide new insights into the molecular mechanisms underlying the contributions of hippocampal subregions to generate this balance.

Structure and function of the hippocampal CA3 module.

The hippocampal formation is crucial for learning and memory, with submodule CA3 thought to be the substrate of pattern completion. However, the underlying synaptic and computational mechanisms of this network are not well understood. Here, we perform circuit reconstruction of a CA3 module using three dimensional (3D) electron microscopy data and combine this with functional connectivity recordings and computational simulations to determine possible CA3 network mechanisms. Direct measurements of connectivity schemes with both physiological measurements and structural 3D EM revealed a high connectivity rate, multi-fold higher than previously assumed. Mathematical modelling indicated that such CA3 networks can robustly generate pattern completion and replay memory sequences. In conclusion, our data demonstrate that the connectivity scheme of the hippocampal submodule is well suited for efficient memory storage and retrieval.

Dorsoventral Heterogeneity of Synaptic Connectivity in Hippocampal CA3 Pyramidal Neurons.

The hippocampal CA3 region plays an important role in learning and memory. CA3 pyramidal neurons (PNs) receive two prominent excitatory inputs-mossy fibers (MFs) from dentate gyrus (DG) and recurrent collaterals (RCs) from CA3 PNs-that play opposing roles in pattern separation and pattern completion, respectively. Although the dorsoventral heterogeneity of the hippocampal anatomy, physiology, and behavior has been well established, nothing is known about the dorsoventral heterogeneity of synaptic connectivity in CA3 PNs. In this study, we performed Timm's sulfide silver staining, dendritic and spine morphological analyses, and ex vivo electrophysiology in mice of both sexes to investigate the heterogeneity of MF and RC pathways along the CA3 dorsoventral axis. Our morphological analyses demonstrate that ventral CA3 (vCA3) PNs possess greater dendritic lengths and more complex dendritic arborization, compared with dorsal CA3 (dCA3) PNs. Moreover, using ChannelRhodopsin2 (ChR2)-assisted patch-clamp recording, we found that the ratio of the RC-to-MF excitatory drive onto CA3 PNs increases substantially from dCA3 to vCA3, with vCA3 PNs receiving significantly weaker MFs, but stronger RCs, excitation than dCA3 PNs. Given the distinct roles of MF versus RC inputs in pattern separation versus completion, our findings of the significant dorsoventral variations of MF and RC excitation in CA3 PNs may have important functional implications for the contribution of CA3 circuit to the dorsoventral difference in hippocampal function.

Neurotrophin-3 from the dentate gyrus supports postsynaptic sites of mossy fiber-CA3 synapses and hippocampus-dependent cognitive functions.

At the center of the hippocampal tri-synaptic loop are synapses formed between mossy fiber (MF) terminals from granule cells in the dentate gyrus (DG) and proximal dendrites of CA3 pyramidal neurons. However, the molecular mechanism regulating the development and function of these synapses is poorly understood. In this study, we showed that neurotrophin-3 (NT3) was expressed in nearly all mature granule cells but not CA3 cells. We selectively deleted the NT3-encoding Ntf3 gene in the DG during the first two postnatal weeks to generate a Ntf3 conditional knockout (Ntf3-cKO). Ntf3-cKO mice of both sexes had normal hippocampal cytoarchitecture but displayed impairments in contextual memory, spatial reference memory, and nest building. Furthermore, male Ntf3-cKO mice exhibited anxiety-like behaviors, whereas female Ntf3-cKO showed some mild depressive symptoms. As MF-CA3 synapses are essential for encoding of contextual memory, we examined synaptic transmission at these synapses using ex vivo electrophysiological recordings. We found that Ntf3-cKO mice had impaired basal synaptic transmission due to deficits in excitatory postsynaptic currents mediated by AMPA receptors but normal presynaptic function and intrinsic excitability of CA3 pyramidal neurons. Consistent with this selective postsynaptic deficit, Ntf3-cKO mice had fewer and smaller thorny excrescences on proximal apical dendrites of CA3 neurons and lower GluR1 levels in the stratum lucidum area where MF-CA3 synapses reside but normal MF terminals, compared with control mice. Thus, our study indicates that NT3 expressed in the dentate gyrus is crucial for the postsynaptic structure and function of MF-CA3 synapses and hippocampal-dependent memory.

Hippocampal ripples signal contextually mediated episodic recall.

High-frequency oscillatory events, termed ripples, represent synchrony of neural activity in the brain. Recent evidence suggests that medial temporal lobe (MTL) ripples support memory retrieval. However, it is unclear if ripples signal the reinstatement of episodic memories. Analyzing electrophysiological MTL recordings from 245 neurosurgical participants performing episodic recall tasks, we find that the rate of hippocampal ripples rises just prior to the free recall of recently formed memories. This prerecall ripple effect (PRE) is stronger in the CA1 and CA3/dentate gyrus (CA3/DG) subfields of the hippocampus than the neighboring MTL regions entorhinal and parahippocampal cortex. PRE is also stronger prior to the retrieval of temporally and semantically clustered, as compared with unclustered, recalls, indicating the involvement of ripples in contextual reinstatement, which is a hallmark of episodic memory.

LRRTM3 regulates activity-dependent synchronization of synapse properties in topographically connected hippocampal neural circuits.

Synaptic cell-adhesion molecules (CAMs) organize the architecture and properties of neural circuits. However, whether synaptic CAMs are involved in activity-dependent remodeling of specific neural circuits is incompletely understood. Leucine-rich repeat transmembrane protein 3 (LRRTM3) is required for the excitatory synapse development of hippocampal dentate gyrus (DG) granule neurons. Here, we report that Lrrtm3-deficient mice exhibit selective reductions in excitatory synapse density and synaptic strength in projections involving the medial entorhinal cortex (MEC) and DG granule neurons, accompanied by increased neurotransmitter release and decreased excitability of granule neurons. LRRTM3 deletion significantly reduced excitatory synaptic innervation of hippocampal mossy fibers (Mf) of DG granule neurons onto thorny excrescences in hippocampal CA3 neurons. Moreover, LRRTM3 loss in DG neurons significantly decreased mossy fiber long-term potentiation (Mf-LTP). Remarkably, silencing MEC-DG circuits protected against the decrease in the excitatory synaptic inputs onto DG and CA3 neurons, excitability of DG granule neurons, and Mf-LTP in Lrrtm3-deficient mice. These results suggest that LRRTM3 may be a critical factor in activity-dependent synchronization of the topography of MEC-DG-CA3 excitatory synaptic connections. Collectively, our data propose that LRRTM3 shapes the target-specific structural and functional properties of specific hippocampal circuits.

Propagation of sharp wave-ripple activity in the mouse hippocampal CA3 subfield in vitro.

Sharp wave-ripple complexes (SPW-Rs) are spontaneous oscillatory events that characterize hippocampal activity during resting periods and slow-wave sleep. SPW-Rs are related to memory consolidation - the process during which newly acquired memories are transformed into long-lasting memory traces. To test the involvement of SPW-Rs in this process, it is crucial to understand how SPW-Rs originate and propagate throughout the hippocampus. SPW-Rs can originate in CA3, and they typically spread from CA3 to CA1, but little is known about their formation within CA3. To investigate the generation and propagation of SPW-Rs in CA3, we recorded from mouse hippocampal slices using multi-electrode arrays and patch-clamp electrodes. We characterized extracellular and intracellular correlates of SPW-Rs and quantified their propagation along the pyramidal cell layer of CA3. We found that a hippocampal slice can be described by a speed and a direction of propagation of SPW-Rs. The preferred propagation direction was from CA3c (the subfield closer to the dentate gyrus) toward CA3a (the subfield at the boundary to CA2). In patch-clamp recordings from CA3 pyramidal neurons, propagation was estimated separately for excitatory and inhibitory currents associated with SPW-Rs. We found that propagation speed and direction of excitatory and inhibitory currents were correlated. The magnitude of the speed of propagation of SPW-Rs within CA3 was consistent with the speed of propagation of action potentials in axons of CA3 principal cells. KEY POINTS: Hippocampal sharp waves are considered important for memory consolidation; therefore, it is of interest to understand the mechanisms of their generation and propagation. Here, we used two different approaches to study the propagation of sharp waves in mouse CA3 in vitro: multi-electrode arrays and multiple single-cell recordings. We find a preferred direction of propagation of sharp waves from CA3c toward CA3a - both in the local field potential and in sharp wave-associated excitatory and inhibitory synaptic activity. The speed of sharp wave propagation is consistent with the speed of action potential propagation along the axons of CA3 pyramidal neurons. These new insights into the dynamics of sharp waves in the CA3 network will inform future experiments and theoretical models of sharp-wave generation mechanisms.

Effects of healthy aging and mnemonic strategies on verbal memory performance across the adult lifespan: Mediating role of posterior hippocampus.

In this study, we aimed to understand the contributions of hippocampal anteroposterior subregions (head, body, tail) and subfields (cornu ammonis 1-3 [CA1-3], dentate gyrus [DG], and subiculum [Sub]) and encoding strategies to the age-related verbal memory decline. Healthy participants were administered the California Verbal Learning Test-II to evaluate verbal memory performance and encoding strategies and underwent 4.7 T magnetic resonance imaging brain scan with subsequent hippocampal subregions and subfields manual segmentation. While total hippocampal volume was not associated with verbal memory performance, we found the volumes of the posterior hippocampus (body) and Sub showed significant effects on verbal memory performance. Additionally, the age-related volume decline in hippocampal body volume contributed to lower use of semantic clustering, resulting in lower verbal memory performance. The effect of Sub on verbal memory was statistically independent of encoding strategies. While total CA1-3 and DG volumes did not show direct or indirect effects on verbal memory, exploratory analyses with DG and CA1-3 volumes within the hippocampal body subregion suggested an indirect effect of age-related volumetric reduction on verbal memory performance through semantic clustering. As semantic clustering is sensitive to age-related hippocampal volumetric decline but not to the direct effect of age, further investigation of mechanisms supporting semantic clustering can have implications for early detection of cognitive impairments and decline.

Selective vulnerability of hippocampal CA1 and CA3 pyramidal cells: What are possible pathomechanisms and should more attention be paid to the CA3 region in future studies?

Transient ischemia and reperfusion selectively damage neurons in brain, with hippocampal pyramidal cells being particularly vulnerable. Even within hippocampus, heterogeneous susceptibility is evident, with higher vulnerability of CA1 versus CA3 neurons described for several decades. Therefore, numerous studies have focused exclusively on CA1. Pediatric cardiac surgery is increasingly focusing on studies of hippocampal structures, and a negative impact of cardiopulmonary bypass on the hippocampus cannot be denied. Recent studies show a shift in selective vulnerability from neurons of CA1 to CA3. This review shows that cell damage is increased in CA3, sometimes stronger than in CA1, depending on several factors (method, species, age, observation period). Despite a highly variable pattern, several markers illustrate greater damage to CA3 neurons than previously assumed. Nevertheless, the underlying cellular mechanisms have not been fully deciphered to date. The complexity is reflected in possible pathomechanisms discussed here, with numerous factors (NMDA, kainate and AMPA receptors, intrinsic oxidative stress potential and various radicals, AKT isoforms, differences in vascular architecture, ratio of pro- and anti-apoptotic Bcl-2 factors, vulnerability of interneurons, mitochondrial dysregulation) contributing to either enhanced CA1 or CA3 vulnerability. Furthermore, differences in expressed genome, proteome, metabolome, and transcriptome in CA1 and CA3 appear to influence differential behavior after damaging stimuli, thus metabolomics-, transcriptomics-, and proteomics-based analyses represent a viable option to identify pathways of selective vulnerability in hippocampal neurons. These results emphasize that future studies should focus on the CA3 field in addition to CA1, especially with regard to improving therapeutic strategies after ischemic/hypoxic brain injury.

Formation and retrieval of cell assemblies in a biologically realistic spiking neural network model of area CA3 in the mouse hippocampus.

The hippocampal formation is critical for episodic memory, with area Cornu Ammonis 3 (CA3) a necessary substrate for auto-associative pattern completion. Recent theoretical and experimental evidence suggests that the formation and retrieval of cell assemblies enable these functions. Yet, how cell assemblies are formed and retrieved in a full-scale spiking neural network (SNN) of CA3 that incorporates the observed diversity of neurons and connections within this circuit is not well understood. Here, we demonstrate that a data-driven SNN model quantitatively reflecting the neuron type-specific population sizes, intrinsic electrophysiology, connectivity statistics, synaptic signaling, and long-term plasticity of the mouse CA3 is capable of robust auto-association and pattern completion via cell assemblies. Our results show that a broad range of assembly sizes could successfully and systematically retrieve patterns from heavily incomplete or corrupted cues after a limited number of presentations. Furthermore, performance was robust with respect to partial overlap of assemblies through shared cells, substantially enhancing memory capacity. These novel findings provide computational evidence that the specific biological properties of the CA3 circuit produce an effective neural substrate for associative learning in the mammalian brain.

CA3 Circuit Model Compressing Sequential Information in Theta Oscillation and Replay.

The hippocampus plays a critical role in the compression and retrieval of sequential information. During wakefulness, it achieves this through theta phase precession and theta sequences. Subsequently, during periods of sleep or rest, the compressed information reactivates through sharp-wave ripple events, manifesting as memory replay. However, how these sequential neuronal activities are generated and how they store information about the external environment remain unknown. We developed a hippocampal cornu ammonis 3 (CA3) computational model based on anatomical and electrophysiological evidence from the biological CA3 circuit to address these questions. The model comprises theta rhythm inhibition, place input, and CA3-CA3 plastic recurrent connection. The model can compress the sequence of the external inputs, reproduce theta phase precession and replay, learn additional sequences, and reorganize previously learned sequences. A gradual increase in synaptic inputs, controlled by interactions between theta-paced inhibition and place inputs, explained the mechanism of sequence acquisition. This model highlights the crucial role of plasticity in the CA3 recurrent connection and theta oscillational dynamics and hypothesizes how the CA3 circuit acquires, compresses, and replays sequential information.

Noncanonical projections to the hippocampal CA3 regulate spatial learning and memory by modulating the feedforward hippocampal trisynaptic pathway.

The hippocampal formation (HF) is well documented as having a feedforward, unidirectional circuit organization termed the trisynaptic pathway. This circuit organization exists along the septotemporal axis of the HF, but the circuit connectivity across septal to temporal regions is less well described. The emergence of viral genetic mapping techniques enhances our ability to determine the detailed complexity of HF circuitry. In earlier work, we mapped a subiculum (SUB) back projection to CA1 prompted by the discovery of theta wave back propagation from the SUB to CA1 and CA3. We reason that this circuitry may represent multiple extended noncanonical pathways involving the subicular complex and hippocampal subregions CA1 and CA3. In the present study, multiple retrograde viral tracing approaches produced robust mapping results, which supports this prediction. We find significant noncanonical synaptic inputs to dorsal hippocampal CA3 from ventral CA1 (vCA1), perirhinal cortex (Prh), and the subicular complex. Thus, CA1 inputs to CA3 run opposite the trisynaptic pathway and in a temporal to septal direction. Our retrograde viral tracing results are confirmed by anterograde-directed viral mapping of projections from input mapped regions to hippocampal dorsal CA3 (dCA3). We find that genetic inactivation of the projection of vCA1 to dCA3 impairs object-related spatial learning and memory but does not modulate anxiety-related behaviors. Our data provide a circuit foundation to explore novel functional roles contributed by these noncanonical hippocampal circuit connections to hippocampal circuit dynamics and learning and memory behaviors.

Conjunctive spatial and self-motion codes are topographically organized in the GABAergic cells of the lateral septum.

The hippocampal spatial code's relevance for downstream neuronal populations-particularly its major subcortical output the lateral septum (LS)-is still poorly understood. Here, using calcium imaging combined with unbiased analytical methods, we functionally characterized and compared the spatial tuning of LS GABAergic cells to those of dorsal CA3 and CA1 cells. We identified a significant number of LS cells that are modulated by place, speed, acceleration, and direction, as well as conjunctions of these properties, directly comparable to hippocampal CA1 and CA3 spatially modulated cells. Interestingly, Bayesian decoding of position based on LS spatial cells reflected the animal's location as accurately as decoding using the activity of hippocampal pyramidal cells. A portion of LS cells showed stable spatial codes over the course of multiple days, potentially reflecting long-term episodic memory. The distributions of cells exhibiting these properties formed gradients along the anterior-posterior and dorsal-ventral axes of the LS, directly reflecting the topographical organization of hippocampal inputs to the LS. Finally, we show using transsynaptic tracing that LS neurons receiving CA3 and CA1 excitatory input send projections to the hypothalamus and medial septum, regions that are not targeted directly by principal cells of the dorsal hippocampus. Together, our findings demonstrate that the LS accurately and robustly represents spatial, directional as well as self-motion information and is uniquely positioned to relay this information from the hippocampus to its downstream regions, thus occupying a key position within a distributed spatial memory network.

Cognitive aging is associated with redistribution of synaptic weights in the hippocampus.

Behaviors that rely on the hippocampus are particularly susceptible to chronological aging, with many aged animals (including humans) maintaining cognition at a young adult-like level, but many others the same age showing marked impairments. It is unclear whether the ability to maintain cognition over time is attributable to brain maintenance, sufficient cognitive reserve, compensatory changes in network function, or some combination thereof. While network dysfunction within the hippocampal circuit of aged, learning-impaired animals is well-documented, its neurobiological substrates remain elusive. Here we show that the synaptic architecture of hippocampal regions CA1 and CA3 is maintained in a young adult-like state in aged rats that performed comparably to their young adult counterparts in both trace eyeblink conditioning and Morris water maze learning. In contrast, among learning-impaired, but equally aged rats, we found that a redistribution of synaptic weights amplifies the influence of autoassociational connections among CA3 pyramidal neurons, yet reduces the synaptic input onto these same neurons from the dentate gyrus. Notably, synapses within hippocampal region CA1 showed no group differences regardless of cognitive ability. Taking the data together, we find the imbalanced synaptic weights within hippocampal CA3 provide a substrate that can explain the abnormal firing characteristics of both CA3 and CA1 pyramidal neurons in aged, learning-impaired rats. Furthermore, our work provides some clarity with regard to how some animals cognitively age successfully, while others' lifespans outlast their "mindspans."

Neuroligin-3-Mediated Synapse Formation Strengthens Interactions between Hippocampus and Barrel Cortex in Associative Memory.

Memory traces are believed to be broadly allocated in cerebral cortices and the hippocampus. Mutual synapse innervations among these brain areas are presumably formed in associative memory. In the present study, we have used neuronal tracing by pAAV-carried fluorescent proteins and neuroligin-3 mRNA knockdown by shRNAs to examine the role of neuroligin-3-mediated synapse formation in the interconnection between primary associative memory cells in the sensory cortices and secondary associative memory cells in the hippocampus during the acquisition and memory of associated signals. Our studies show that mutual synapse innervations between the barrel cortex and the hippocampal CA3 region emerge and are upregulated after the memories of associated whisker and odor signals come into view. These synapse interconnections are downregulated by a knockdown of neuroligin-3-mediated synapse linkages. New synapse interconnections and the strengthening of these interconnections appear to endorse the belief in an interaction between the hippocampus and sensory cortices for memory consolidation.

The ZIP3 Zinc Transporter Is Localized to Mossy Fiber Terminals and Is Required for Kainate-Induced Degeneration of CA3 Neurons.

Tight regulation of neuronal Zn2+ is critical for physiological function. Multiple Zn2+ transporters are expressed in the brain, yet their spatial distribution and distinct roles are largely unknown. Here, we show developmental regulation of the expression of Zn2+ transporters ZIP1 and ZIP3 in mouse hippocampal neurons, corresponding to previously described increase in neuronal vesicular Zn2+ during the first postnatal month. Rates of Zn2+ uptake in cultured mouse hippocampal neurons, monitored using FluoZin-3 fluorescence, were higher in mature neurons, which express higher levels of ZIP1 and ZIP3. Zn2+ uptake was attenuated by ∼50% following silencing of either ZIP1 or ZIP3. Expression of both ZIP1 and ZIP3 was ubiquitous on somas and most neuronal processes in the cultured neurons. In contrast, we observed distinct localization of the transporters in adult mouse hippocampal brain, with ZIP1 predominantly expressed in the CA3 stratum pyramidale, and ZIP3 primarily localized to the stratum lucidum. Consistent with their localization, silencing of ZIP1 expression in vivo reduced Zn2+ uptake in CA3 neurons while ZIP3 silencing reduced Zn2+ influx into dentate gyrus (DG) granule cells in acute hippocampal slices. Strikingly, in vivo silencing of ZIP3, but not ZIP1, protected CA3 neurons from neurodegeneration following kainate-induced seizures. Our results indicate that distinct Zn2+ transporters control Zn2+ accumulation and toxicity in different neuronal populations in the hippocampus and suggest that selective regulation of Zn2+ transporters can prevent seizure induced brain damage.SIGNIFICANCE STATEMENT Zinc plays a major role in neuronal function and its dysregulation is associated with neurodegeneration. Multiple zinc transporters are expressed in neurons, yet little is known on their distinct roles. Here, we show that the plasma membrane ZIP1 and ZIP3 zinc transporters are expressed on distinct neuronal populations in the CA3 region of the hippocampus. We show that ZIP1 mediates zinc influx into postsynaptic cells, while ZIP3 is responsible for zinc re-uptake from this synapse into dentate granule cells. We further show that silencing of ZIP3, but not ZIP1, can rescue the postsynaptic cells from kainate-induced neurodegeneration. This suggests that neuronal zinc toxicity and degeneration can be modulated by regulation of specific zinc transporters function.

CA2 orchestrates hippocampal network dynamics.

The hippocampus is composed of various subregions: CA1, CA2, CA3, and the dentate gyrus (DG). Despite the abundant hippocampal research literature, until recently, CA2 received little attention. The development of new genetic and physiological tools allowed recent studies characterizing the unique properties and functional roles of this hippocampal subregion. Despite its small size, the cellular content of CA2 is heterogeneous at the molecular and physiological levels. CA2 has been heavily implicated in social behaviors, including social memory. More generally, the mechanisms by which the hippocampus is involved in memory include the reactivation of neuronal ensembles following experience. This process is coordinated by synchronous network events known as sharp-wave ripples (SWRs). Recent evidence suggests that CA2 plays an important role in the generation of SWRs. The unique connectivity and physiological properties of CA2 pyramidal cells make this region a computational hub at the core of hippocampal information processing. Here, we review recent findings that support the role of CA2 in coordinating hippocampal network dynamics from a systems neuroscience perspective.

BDNF and Lactate as Modulators of Hippocampal CA3 Network Physiology.

Growing evidence supports the notion that brain-derived neurotrophic factor (BDNF) and lactate are potent modulators of mammalian brain function. The modulatory actions of those biomolecules influence a wide range of neuronal responses, from the shaping of neuronal excitability to the induction and expression of structural and synaptic plasticity. The biological actions of BDNF and lactate are mediated by their cognate receptors and specific transporters located in the neuronal membrane. Canonical functions of BDNF occur via the tropomyosin-related kinase B receptor (TrkB), whereas lactate acts via monocarboxylate transporters or the hydroxycarboxylic acid receptor 1 (HCAR1). Both receptors are highly expressed in the central nervous system, and some of their physiological actions are particularly well characterized in the hippocampus, a brain structure involved in the neurophysiology of learning and memory. The multifarious neuronal circuitry between the axons of the dentate gyrus granule cells, mossy fibers (MF), and pyramidal neurons of area CA3 is of great interest given its role in specific mnemonic processes and involvement in a growing number of brain disorders. Whereas the modulation exerted by BDNF via TrkB has been extensively studied, the influence of lactate via HCAR1 on the properties of the MF-CA3 circuit is an emerging field. In this review, we discuss the role of both systems in the modulation of brain physiology, with emphasis on the hippocampal CA3 network. We complement this review with original data that suggest cross-modulation is exerted by these two independent neuromodulatory systems.

The dorsal hippocampal CA3 regulates spatial reference memory through the CtBP2/GluR2 pathway.

The dorsal hippocampus plays a pivotal role in spatial memory. However, the role of subregion-specific molecular pathways in spatial cognition remains unclear. We observed that the transcriptional coregulator C-terminal binding protein 2 (CtBP2) presented CA3-specific enrichment in expression. RNAi interference of CtBP2 in the dorsal CA3 (dCA3) neurons, but not the ventral CA3 (vCA3), specifically impaired spatial reference memory and reduced the expression of GluR2, the calcium permeability determinant subunit of AMPA receptors. Application of an antagonist for GluR2-absent calcium permeable AMPA receptors rescued spatial memory deficits in dCA3 CtBP2 knockdown animals. Transcriptomic analysis suggest that CtBP2 may regulate GluR2 protein level through post-translational mechanisms, especially by the endocytosis pathway which regulates AMPA receptor sorting. Consistently, CtBP2 deficiency altered the mRNA expression of multiple endocytosis-regulatory genes, and CtBP2 knockdown in primary hippocampal neurons enhanced GluR2-containing AMPA receptor endocytosis. Together, our results provide evidence that the dCA3 regulates spatial reference memory by the CtBP2/GluR2 pathway through the modulation of calcium permeable AMPA receptors.

Cell type-specific mechanisms of information transfer in data-driven biophysical models of hippocampal CA3 principal neurons.

The transformation of synaptic input into action potential output is a fundamental single-cell computation resulting from the complex interaction of distinct cellular morphology and the unique expression profile of ion channels that define the cellular phenotype. Experimental studies aimed at uncovering the mechanisms of the transfer function have led to important insights, yet are limited in scope by technical feasibility, making biophysical simulations an attractive complementary approach to push the boundaries in our understanding of cellular computation. Here we take a data-driven approach by utilizing high-resolution morphological reconstructions and patch-clamp electrophysiology data together with a multi-objective optimization algorithm to build two populations of biophysically detailed models of murine hippocampal CA3 pyramidal neurons based on the two principal cell types that comprise this region. We evaluated the performance of these models and find that our approach quantitatively matches the cell type-specific firing phenotypes and recapitulate the intrinsic population-level variability in the data. Moreover, we confirm that the conductance values found by the optimization algorithm are consistent with differentially expressed ion channel genes in single-cell transcriptomic data for the two cell types. We then use these models to investigate the cell type-specific biophysical properties involved in the generation of complex-spiking output driven by synaptic input through an information-theoretic treatment of their respective transfer functions. Our simulations identify a host of cell type-specific biophysical mechanisms that define the morpho-functional phenotype to shape the cellular transfer function and place these findings in the context of a role for bursting in CA3 recurrent network synchronization dynamics.