Atypical perineuronal nets in the CA2 region interfere with social memory in a mouse model of social dysfunction

Abstract

Social memory dysfunction is an especially devastating symptom of many neuropsychiatric disorders, which makes understanding the cellular and molecular processes that contribute to such abnormalities important. Evidence suggests that the hippocampus, particularly the CA2 region, plays an important role in social memory. We sought to identify potential mechanisms of social memory dysfunction in the hippocampus by investigating features of neurons, glia, and the extracellular matrix (ECM) of BTBR mice, an inbred mouse strain with deficient social memory. The CA2 is known to receive inputs from dentate gyrus adult-born granule cells (abGCs), neurons known to participate in social memory, so we examined this cell population and found fewer abGCs, as well as fewer axons from abGCs in the CA2 of BTBR mice compared to controls. We also found that BTBR mice had fewer pyramidal cell dendritic spines, in addition to fewer microglia and astrocytes, in the CA2 compared to controls. Along with diminished neuronal and glial elements, we found atypical perineuronal nets (PNNs), specialized ECM structures that regulate plasticity, in the CA2 of BTBR mice. By diminishing PNNs in the CA2 of BTBR mice to control levels, we observed a partial restoration of social memory. Our findings suggest that the CA2 region of BTBR mice exhibits multiple cellular and extracellular abnormalities and identify atypical PNNs as one mechanism producing social memory dysfunction, although the contribution of reduced abGC afferents, pyramidal cell dendritic spine and glial cell numbers remains unexplored.

Structural and Functional Deviations of the Hippocampus in Schizophrenia and Schizophrenia Animal Models

“…Interestingly, the authors could observe a region-specific reduction in the number of PNNs and PNN-wearing parvalbumin-positive neurons especially in the CA1-subfield of the hippocampus [ 295 ]. In addition, the presence of atypical perineuronal nets in the CA2-subfield was observed to be associated with a dysfunction of the social memory [ 296 ]. In this perspective, the targeting of perineuronal nets might be an interesting approach with regard to the functional deficits of the hippocampus in schizophrenia and schizophrenia animal models.…”

“…In this perspective, the targeting of perineuronal nets might be an interesting approach with regard to the functional deficits of the hippocampus in schizophrenia and schizophrenia animal models. The manipulation of perineuronal nets in the CNS was frequently performed by the stereotactic administration of bacterially-derived chondroitinase ABC (ChABC) or hyaluronidase in rodents [ 271 , 274 , 275 , 296 , 297 , 298 , 299 , 300 ]. Intriguingly, the experimental digestion of PNNs by ChABC-injections in the ventral hippocampus raised the general hippocampal activity, increased the activity of dopaminergic neurons and augmented the locomotor response to amphetamine indicating possible implications for schizophrenia [ 301 ].…”

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

“…To assess social discrimination, two versions of the direct social interaction test were adapted from previously established protocols (Hitti and Siegelbaum, 2014; Smith et al, 2016; Cope et al, 2020; 2021). Each version of this test consisted of two or three social stimulus trials, each separated by 24 hr.…”

“…The testing was conducted in low lighting in an open-field box (23 x 25 x 25 cm). For 5 min, twice per day, for 3 days, mice were habituated to the testing arena as previously described (Cope et al, 2018a(Cope et al, , 2018b(Cope et al, , 2021. Mice were habituated to the objects on the third day of habituations.…”

How Stress Influences the Dynamic Plasticity of the Brain’s Extracellular Matrix

“…In some cases, PNNs have been associated with increased firing of neurons they surround, which are primarily parvalbumin+ inhibitory interneurons in the neocortex and hippocampus (Sorg et al, 2016;Wingert and Sorg, 2021). The functional consequences of PNNs seem to differ depending on brain region, cell type, and behavioral task, with some studies showing that PNNs facilitate learning and memory, while others show they have an inhibitory effect on these processes (Paylor et al, 2018;Anderson et al, 2020;Carulli et al, 2020;Cope et al, 2021;Wingert and Sorg, 2021). The overall picture that is emerging is one that is common in biology-an inverted U-shaped curve exists where atypically low or high PNNs impair function.…”