Intrinsic and extrinsic wiring of CA3: Indications for connectional heterogeneity

Witter, Menno P.

doi:10.1101/lm.725207

Cited by 206 publications

(213 citation statements)

References 102 publications

(156 reference statements)

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“…The altered innervation of CA3 neurons is expected to affect functional connectivity, because axosomatic synapses may be more efficient than axodendritic synapses in driving discharge (38). Alterations in axonal patterning, in addition to changes in dendritic growth both early in neonatal development and in the adult brain, may cumulatively impinge on the structure and function of this neural network.…”

Section: Discussionmentioning

confidence: 99%

Altered axonal targeting and short-term plasticity in the hippocampus of Disc1 mutant mice

Kvajo

McKellar

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

106

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Carefully designed animal models of genetic risk factors are likely to aid our understanding of the pathogenesis of schizophrenia. Here, we study a mouse strain with a truncating lesion in the endogenous Disc1 ortholog designed to model the effects of a schizophreniapredisposing mutation and offer a detailed account of the consequences that this mutation has on the development and function of a hippocampal circuit. We uncover widespread and cumulative cytoarchitectural alterations in the dentate gyrus during neonatal and adult neurogenesis, which include errors in axonal targeting and are accompanied by changes in short-term plasticity at the mossy fiber/CA3 circuit. We also provide evidence that cAMP levels are elevated as a result of the Disc1 mutation, leading to altered axonal targeting and dendritic growth. The identified structural alterations are, for the most part, not consistent with the growthpromoting and premature maturation effects inferred from previous RNAi-based Disc1 knockdown. Our results provide support to the notion that modest disturbances of neuronal connectivity and accompanying deficits in short-term synaptic dynamics is a general feature of schizophrenia-predisposing mutations. psychiatric disease | rare mutation | mouse model T he schizophrenia (SCHZ) susceptibility gene DISC1 was identified through a balanced chromosomal translocation (1;11)(q42.1;q14.3) segregating with SCHZ and mood disorders in a large Scottish pedigree. This is the only confirmed disease risk allele within the DISC1 locus. The biology of DISC1 is being interrogated with a variety of approaches, such as acute RNAimediated gene knockdown (1-4), overexpression of truncated forms of the human DISC1 (5, 6), and chemical mutagenesis (7). Although they provide information about potential pathways related to DISC1, these approaches are not meant to recapitulate the integrated effects of the pathogenic translocation, and the relevance of these findings to SCHZ pathogenesis remains uncertain.We used a disease-focused knockin approach to introduce a truncating lesion in the endogenous murine Disc1 ortholog designed to model the effects of the (1;11) translocation (Mouse Genome Informatics nomenclature Disc1 Tm1Kara ) (8, 9). Although the divergence in the human and mouse Disc1 gene does not allow an exact replication of the human translocation, this mouse model approximates very closely the Scottish mutation. One advantage of our approach is that it retains endogenous levels as well as spatial and temporal patterns of Disc1 expression, and it preserves short N-terminal isoforms that are presumably unaffected by the Scottish translocation and seem to be expressed at relatively higher levels in the hippocampus (HPC) of patients with SCHZ (10). A comprehensive behavioral analysis has shown that Disc1 Tm1Kara mice display a unique profile of cognitive impairments, including specific and robust deficiencies in working memory (WM) tests (8, 9), which may relate to similar cognitive deficits prominent in psychotic disorders.DISC1 is...

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Section: Discussionmentioning

confidence: 99%

Altered axonal targeting and short-term plasticity in the hippocampus of Disc1 mutant mice

Kvajo

McKellar

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

106

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“…In the rat, intra-CA3 (as opposed to CA3-CA1) recurrent connections are particularly dominant in ventral hippocampus [101] -yet another indication of longitudinal, dorsal-ventral gradients in hippocampal connectivity, and an important reminder that 2D slices must ultimately be related to the 3D context of the in vivo brain. Back-projections from CA3 to DG also vary in density and targets along the longitudinal axis, becoming increasingly prevalent in ventral hippocampus [102] and further confounding views of the hippocampal circuit as a single loop.…”

Section: Box 1: Thinking In 3-dmentioning

confidence: 99%

Updating hippocampal representations: CA2 joins the circuit

Jones

McHugh

2011

Trends in Neurosciences

114

106

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The hippocampus integrates the encoding, storage and recall of memories, binding the spatiotemporal and sensory information that constitutes experience and keeping episodes in their correct context. The rapid and accurate processing of such daunting volumes of continuouslychanging data relies on dynamically assigning different aspects of mnemonic processing to specialized, interconnected networks corresponding to the anatomical subfields of dentate gyrus (DG), CA3 and CA1. However, differentially processed information ultimately has to be reintegrated into conjunctive representations, and this is unlikely to be achieved by unidirectional, sequential steps through a DG-CA3-CA1 loop. In this Review, we highlight recently discovered anatomical and physiological features that are likely to necessitate updates to the hippocampal circuit diagram, particularly by incorporating the oft-neglected CA2 region.3

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“…To achieve this, we used a SONET algorithm (34), setting recip, conv, div, and chain to values > 0, where  describes the enrichment of a given motif above the random level. Finally, in a subset of simulations, connectivity was restricted to two thirds of the network by eliminating connections from the matrix W, to account for the limited extent of CA3 pyramidal neuron axons along the septo-temporal axis (35,36) (fig. S10).…”

Section: Modeling Basic Structure Of the Ca3 Network Modelmentioning

confidence: 99%

Synaptic mechanisms of pattern completion in the hippocampal CA3 network

Guzman

Schlögl

Frotscher

et al. 2016

Science

236

289

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The hippocampal CA3 region plays a key role in learning and memory. Recurrent CA3-CA3 synapses are thought to be the subcellular substrate of pattern completion. However, the synaptic mechanisms of this network computation remain enigmatic. To investigate these mechanisms, we combined functional connectivity analysis with network modeling.Simultaneous recording from up to eight CA3 pyramidal neurons revealed that connectivity was sparse, spatially uniform, and highly enriched in disynaptic motifs (reciprocal, convergence, divergence, and chain motifs). Unitary connections were comprised of one or two synaptic contacts, suggesting efficient use of postsynaptic space. Real-size modeling indicated that CA3 networks with sparse connectivity, disynaptic motifs, and single-contact connections robustly generated pattern completion. Thus, macro-and microconnectivity contribute to efficient memory storage and retrieval in hippocampal networks. 3The hippocampal CA3 region plays a key role in learning and memory (1)(2)(3)(4)(5). A hallmark property of the network is its ability to retrieve patterns from partial or noisy cues, a process referred to as autoassociative recall, attractor dynamics, or pattern completion (3-7). However, the synaptic mechanisms underlying pattern completion have remained enigmatic. Previous neuronal network models suggested that recurrent CA3-CA3 pyramidal cell synapses play a key role in this process (8)(9)(10)(11)(12)(13)(14). In the storage phase, a stimulus pattern will activate an ensemble of interconnected neurons and induce synaptic potentiation in the corresponding recurrent synapses. In the recall phase, a partial pattern will initially activate only a fraction of the ensemble, but subsequently recruit the remaining cells via potentiated synapses. Successful pattern completion requires sufficient synaptic efficacy and network connectivity (12, 14). Whether the biological properties of the CA3 network are consistent with these assumptions remains unclear. Analysis of functional connectivity in the CA3 networkThe CA3 network is often envisaged as a network of highly interconnected neurons (3-5, 8, 11). To test this hypothesis, we analyzed functional connectivity by simultaneous recordings from up to eight CA3 pyramidal neurons in rat brain in vitro, followed by selective biocytin labeling ( 4 Macroconnectivity in the CA3 networkOur results suggested that connectivity in the CA3 cell network was surprisingly sparse, with a mean connection probability of 0.92%. Both experimental data and simulations using fully reconstructed CA3 neurons labeled in vivo indicated that connectivity was only moderately dependent on slice orientation (materials and methods; fig. S3). However, connectivity may decline with distance (17).Furthermore, connectivity might be non-random, with ensembles of highly connected cells embedded in a sparsely connected population (18, 19). To test these hypotheses, we first examined whether the connection probability was dependent on intersomatic distance (Fig. 2A). The ave...

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Intrinsic and extrinsic wiring of CA3: Indications for connectional heterogeneity

Cited by 206 publications

References 102 publications

Altered axonal targeting and short-term plasticity in the hippocampus of Disc1 mutant mice

Altered axonal targeting and short-term plasticity in the hippocampus of Disc1 mutant mice

Updating hippocampal representations: CA2 joins the circuit

Synaptic mechanisms of pattern completion in the hippocampal CA3 network

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