Structure and function of the hippocampal CA3 module

Sammons, Rosanna P.; Vezir, Mourat; Moreno-Velasquez, Laura; Cano, Gaspar; Orlando, Marta; Sievers, Meike; Grasso, Eleonora; Metodieva, Verjinia D.; Kempter, Richard; Schmidt, Helene; Schmitz, Dietmar

doi:10.1073/pnas.2312281120

Cited by 5 publications

(4 citation statements)

References 53 publications

(87 reference statements)

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“…2B ). No intersomatic distance dependence of connectivity was observed either, in line with other reports in the CA3 of rats, mice, and humans (Guzman et al, 2016; Sammons et al, 2024; Watson et al, 2024) ( Fig. 2E, Supplementary Fig.…”

Section: Resultssupporting

confidence: 92%

“…We next examined excitatory postsynaptic potential (EPSP) properties. As previously observed in multiple species, (Guzman et al, 2016;Miles and Wong, 1986;Sammons et al, 2024;Watson et al, 2024), CA3-CA3 synapses are relatively weak, with mean unitary depolarisations across all subclasses of just 0.94 ± 0.10 mV (Fig. 3E).…”

Section: Similar Synaptic Properties Of Unitary Connections Between C...supporting

confidence: 83%

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Cell-specific wiring routes information flow through hippocampal CA3

Watson,

Vargas-Barroso,

Jonas

2024

Preprint

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The hippocampus is dogmatically described as a trisynaptic circuit. Dentate gyrus granule cells, CA3 pyramidal neurons (PNs), and CA1 PNs are serially connected, forming a circuit that critically enables memory storage in the brain. However, fundamental aspects of hippocampal function go beyond this simplistic ‘trisynaptic’ definition. CA3 PNs connect not only to CA1, but also establish the largest autoassociative network in the brain. In addition, CA3 PNs are not uniform, differing in their morphology, intrinsic properties, and even the extent of granule cell input. Understanding how these different subtypes of CA3 PNs are embedded in the hippocampal network is essential for our quest to understand learning and memory. Here, we performed simultaneous multi-cellular patch-clamp recordings from up to eight CA3 PNs in acute mouse hippocampal slices, testing 3114 possible connections between identified cells. Combined with post-hoc morphological analysis, this allowed full characterization of neuronal heterogeneity in functioning microcircuits. We demonstrate that CA3 PNs can be divided into distinct ‘deep’ and ‘superficial’ subclasses, with altered input-output balance. While both subtypes formed recurrent connectivity within classes, connectivity between subtypes was surprisingly asymmetric. Recurrent connectivity was abundant from superficial to deep, but almost absent from deep to superficial PNs, thereby splitting CA3 into parallel recurrent networks which will allow more complex information processing. Finally, we observed innervation of PN subclasses by distinct interneurons, a potential mechanism to gate information flow through CA3 sublayers. Together, our data present a major revision to the classical ‘trisynaptic’ view of the hippocampus, bringing us closer to understanding its complex action in information storage.

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Section: Resultssupporting

confidence: 92%

Section: Similar Synaptic Properties Of Unitary Connections Between C...supporting

confidence: 83%

Cell-specific wiring routes information flow through hippocampal CA3

Watson,

Vargas-Barroso,

Jonas

2024

Preprint

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“…Sparse CA3 synaptic connectivity was previously demonstrated, in both rats (Guzman et al, 2016) and guinea-pigs (Miles and Wong, 1986). However, surprisingly high CA3 connectivity has recently been reported in mice (Sammons et al, 2024). To quantitatively analyze synaptic connectivity across species, we compared connection probability among humans, rats, and mice ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Human hippocampal CA3 uses specific functional connectivity rules for efficient associative memory

Watson,

Vargas-Barroso,

Morse-Mora

et al. 2024

Preprint

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The human brain has remarkable computational power. It generates sophisticated behavioral sequences, stores engrams over an individual's lifetime, and produces higher cognitive functions up to the level of consciousness. However, so little of our neuroscience knowledge covers the human brain, and it remains unknown whether this organ is truly unique, or is a scaled version of the extensively studied rodent brain. To address this fundamental question, we determined the cellular, synaptic, and connectivity rules of the hippocampal CA3 recurrent circuit using multicellular patch clamp-recording. This circuit is the largest autoassociative network in the brain, and plays a key role in memory and higher-order computations such as pattern separation and pattern completion. We demonstrate that human hippocampal CA3 employs sparse connectivity, in stark contrast to neocortical recurrent networks. Connectivity sparsifies from rodents to humans, providing a circuit architecture that maximizes associational power. Unitary synaptic events at human CA3–CA3 synapses showed both distinct species-specific and circuit-dependent properties, with high reliability, unique amplitude precision, and long integration times. We also identify differential scaling rules between hippocampal pathways from rodents to humans, with a moderate increase in the convergence of CA3 inputs per cell, but a marked increase in human mossy fiber innervation. Anatomically guided full-scale modeling suggests that the human brain's sparse connectivity, expanded neuronal number, and reliable synaptic signaling combine to enhance the associative memory storage capacity of CA3. Together, our results reveal unique rules of connectivity and synaptic signaling in the human hippocampus, demonstrating the absolute necessity of human brain research and beginning to unravel the remarkable performance of our autoassociative memory circuits.

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“…[82] estimated based on experimental studies [83] that a single hypercolumn in primate V1 receives only 10-30 feedforward inputs from the magnocellular layer of dorsal LGN mediating retinal input, with single cells in L4 α receiving as little as 0 - 6 inputs. Also in the hippocampal region CA3, where place fields are enlarged compared to the upstream dentate gyrus [40], the recurrent connectivity is high [78, 84].…”

Section: Discussionmentioning

confidence: 99%

Cooperative coding of continuous variables in networks with sparsity constraint

Züge,

Memmesheimer

2024

Preprint

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A hallmark of biological and artificial neural networks is that neurons tile the range of continuous sensory inputs and intrinsic variables with overlapping responses. It is characteristic for the underlying recurrent connectivity in the cortex that neurons with similar tuning predominantly excite each other. The reason for such an architecture is not clear. Using an analytically tractable model, we show that it can naturally arise from a cooperative coding scheme. In this scheme neurons with similar responses specifically support each other by sharing their computations to obtain the desired population code. This sharing allows each neuron to effectively respond to a broad variety of inputs, while only receiving few feedforward and recurrent connections. Few strong, specific recurrent connections then replace many feedforward and less specific recurrent connections, such that the resulting connectivity optimizes the number of required synapses. This suggests that the number of required synapses may be a crucial constraining factor in biological neural networks. Synaptic savings increase with the dimensionality of the encoded variables. We find a trade-off between saving synapses and response speed. The response speed improves by orders of magnitude when utilizing the window of opportunity between excitatory and delayed inhibitory currents that arises if, as found in experiments, spike frequency adaptation is present or strong recurrent excitation is balanced by strong, shortly-lagged inhibition.

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Structure and function of the hippocampal CA3 module

Cited by 5 publications

References 53 publications

Cell-specific wiring routes information flow through hippocampal CA3

Cell-specific wiring routes information flow through hippocampal CA3

Human hippocampal CA3 uses specific functional connectivity rules for efficient associative memory

Cooperative coding of continuous variables in networks with sparsity constraint

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