A direct lateral entorhinal cortex to hippocampal CA2 circuit conveys social information required for social memory

Lopez‐Rojas, Jeffrey; Solı́s, Christopher; Leroy, Félix; Kandel, Eric R.; Siegelbaum, S. A.

doi:10.1016/j.neuron.2022.01.028

Cited by 76 publications

(65 citation statements)

References 68 publications

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“…VGLUT1 labels axons from CA3 and entorhinal cortex pyramidal cells (Balschun et al, 2010; Zander et al, 2010; Heise et al, 2016), as well as from dentate gyrus granule cells (Heise et al, 2016). Since the CA3, entorhinal cortex, and dentate gyrus each directly project to the CA2 (Kohara et al, 2014; Middleton and McHugh, 2020) and each have been linked to social memory (Chiang et al, 2018; Leung et al, 2018; Lopez-Rojas et al, 2022), we analyzed intensity of VGLUT1 labeling in the CA2 and found no difference between WT and Shank3B KO mice (Figure 1H, Supplementary Table 1). Because Shank3 protein is especially concentrated in mossy fibers (Heise et al, 2016), we examined intensity of zinc transporter 3 (ZnT3), which labels mossy fibers and their synaptic vesicles, in the CA2 and also found no difference between WT and Shank3B KO mice (Figure 1I, Supplementary Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…Additional studies have identified afferents to the CA2 as being involved in these functions. In particular, projections from the SUM and the cholinergic medial septum have been linked to novelty recognition (Chen et al, 2020; Wu et al, 2021; Pimpinella et al, 2021), whereas those from the vasopressinergic paraventricular nucleus, the entorhinal cortex, and the dentate gyrus seem more likely associated with memory of familiar social stimuli (Smith et al, 2016; Lopez-Rojas et al, 2022; Cope et al, 2020). Despite the fact that Shank3, a synaptic scaffolding protein, is expressed in the hippocampus, we found no differences between WT and Shank3B KO mice in markers of several of these afferents to the CA2.…”

Section: Discussionmentioning

confidence: 99%

“…These afferents are both extrahippocampal, from the supramammillary nucleus and paraventricular nucleus of the hypothalamus, the cholinergic basal forebrain, and the entorhinal cortex, and also intrahippocampal, from the dentate gyrus and CA3 region. Taken together, the CA2 and these afferents play important roles in social recognition (Dudek et al, 2016; Raam et al, 2017; Piskorowski and Chevaleyre, 2018; Chiang et al, 2018; Chen et al, 2020; Lopez-Rojas et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

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Activation of the CA2-vCA1 pathway reverses social discrimination dysfunction inShank3Bknockout mice

Cope

Wang

Waters

et al. 2022

Preprint

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Social memory dysfunction is a feature of several neuropsychiatric and neurodevelopmental disorders. Mutation or deletion of the SHANK3 gene, which codes for a synaptic scaffolding protein, has been linked to autism spectrum disorder (ASD) and Phelan-McDermid syndrome, conditions associated with impairments in social memory. Shank3B knockout (KO) mice exhibit several behavioral abnormalities that may be analogous to symptoms of ASD, including social discrimination deficits. The CA2 region of the hippocampus integrates numerous afferents and sends a major output to the ventral CA1 (vCA1), circuitry that plays an important role in social memory. Despite finding few differences in excitatory afferents to the CA2 in Shank3B KO mice, chemogenetic activation of CA2 excitatory neurons restored social recognition function to wildtype (WT) levels. Specific activation of the CA2-vCA1 circuitry had a similar effect. Neuronal oscillations in the theta, gamma and, sharp wave ripple ranges have been linked to social memory, but we observed no differences in these measures between WT and Shank3B KO mice in the vCA1 in response to social stimuli. However, activation of CA2 excitatory neurons enhanced vCA1 theta power in Shank3B KO mice, concurrent with behavioral improvements. These findings suggest that stimulating adult circuitry in a mouse model with neurodevelopmental impairments can be sufficient to invoke latent function, particularly with respect to social memory dysfunction. The extent to which vCA1 network oscillations in the theta range are responsible for rescued behavioral function remains unknown.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Activation of the CA2-vCA1 pathway reverses social discrimination dysfunction inShank3Bknockout mice

Cope

Wang

Waters

et al. 2022

Preprint

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“…This is consistent with the asymmetric pattern of MCU-labeled mitochondrial morphology in CA2 dendrites. Notably, input from the LECII, but not the MECII, carries social information relevant to social recognition memory (Lopez-Rojas et al 2022). Taken together, CA2 SLM may have higher expression of MCU and greater mitochondrial mass than CA1 SLM in order to metabolically support more numerous and more active synapses.…”

Section: Potential Functional Roles For a Distinct Subpopulation Of M...mentioning

confidence: 96%

Layer-specific mitochondrial diversity across hippocampal CA2 dendrites

Pannoni

Gil

Campbell

et al. 2021

Preprint

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CA2 is an understudied subregion of the hippocampus that is critical for social memory. Previous studies identified multiple components of the mitochondrial calcium uniporter (MCU) complex as selectively enriched in CA2, however the functional significance of this enrichment remains unclear. The MCU complex regulates calcium entry into mitochondria, which in turn regulates mitochondrial transport and localization to active synapses. We found that MCU is strikingly enriched in CA2 distal apical dendrites, precisely where CA2 neurons receive entorhinal cortical input carrying social information. Further, MCU-enriched mitochondria in CA2 distal dendrites are larger compared to mitochondria in CA2 proximal apical dendrites and neighboring CA1 apical dendrites. Genetic knockdown of MCU in CA2 resulted in smaller mitochondria in CA2 distal dendrites, indicating that MCU expression plays a role in regulating mitochondrial mass in CA2. MCU overexpression in neighboring CA1 led to larger mitochondria preferentially in proximal dendrites compared to distal dendrites and GFP controls. Our findings demonstrate that mitochondria are molecularly and structurally diverse across hippocampal cell types and circuits, and that MCU expression cell-autonomously regulates mitochondrial mass, but layer-specific dendritic localization depends on cell type. Our data support the idea that CA2 mitochondria are functionally distinct from CA1 mitochondria, which may confer unique synaptic and circuit properties underlying CA2 function in social memory.

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“…Cholinergic, glutamatergic and GABAergic inputs project in turn to the medial and lateral portions of the EC (Gonzalez-Sulser et al, 2014;Fuchs et al, 2016;Desikan et al, 2018;Viney et al, 2018). This loop may control the integration of sensory inputs relevant for social memory as the lateral part of the EC projecting to CA2 region has been recently shown to convey sensory information for this cognitive function (Lopez-Rojas et al, 2022). The Medial Septum as a social recognition hub.…”

Section: Introductionmentioning

confidence: 99%

Medial septum: relevance for social memory

Griguoli

Pimpinella

2022

Front. Neural Circuits

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Animal species are named social when they develop the capability of complex behaviors based on interactions with conspecifics that include communication, aggression, mating and parental behavior, crucial for well-being and survival. The underpinning of such complex behaviors is social memory, namely the capacity to discriminate between familiar and novel individuals. The Medial Septum (MS), a region localized in the basal forebrain, is part of the brain network involved in social memory formation. MS receives several cortical and subcortical synaptic and neuromodulatory inputs that make it an important hub in processing social information relevant for social memory. Particular attention is paid to synaptic inputs that control both the MS and the CA2 region of the hippocampus, one of the major MS output, that has been causally linked to social memory. In this review article, we will provide an overview of local and long range connectivity that allows MS to integrate and process social information. Furthermore, we will summarize previous strategies used to determine how MS controls social memory in different animal species. Finally, we will discuss the impact of an altered MS signaling on social memory in animal models and patients affected by neurodevelopmental and neurodegenerative disorders, including autism and Alzheimer’s Disease.

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A direct lateral entorhinal cortex to hippocampal CA2 circuit conveys social information required for social memory

Cited by 76 publications

References 68 publications

Activation of the CA2-vCA1 pathway reverses social discrimination dysfunction inShank3Bknockout mice

Activation of the CA2-vCA1 pathway reverses social discrimination dysfunction inShank3Bknockout mice

Layer-specific mitochondrial diversity across hippocampal CA2 dendrites

Medial septum: relevance for social memory

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