Parvalbumin Interneurons and Perineuronal Nets in the Hippocampus and Retrosplenial Cortex of Adult Male Mice After Early Social Isolation Stress and Perinatal NMDA Receptor Antagonist Treatment.

Patrycja Klimczak,Yaiza Gramuntell,Arianna Rizzo,Marta Perez-Rando,Juan Nacher,Esther Castillo-Gómez,Marc Beltran

doi:10.3389/fnsyn.2021.733989

Abstract

Both early life aversive experiences and intrinsic alterations in early postnatal neurodevelopment are considered predisposing factors for psychiatric disorders, such as schizophrenia. The prefrontal cortex and the hippocampus have protracted postnatal development and are affected in schizophrenic patients. Interestingly, similar alterations have been observed in the retrosplenial cortex (RSC). Studies in patients and animal models of schizophrenia have found alterations in cortical parvalbumin (PV) expressing interneurons, making them good candidates to study the etiopathology of this disorder. Some of the alterations observed in PV+ interneurons may be mediated by perineuronal nets (PNNs), specialized regions of the extracellular matrix, which frequently surround these inhibitory neurons. In this study, we have used a double hit model (DHM) combining a single perinatal injection of an NMDAR antagonist (MK801) to disturb early postnatal development and post-weaning social isolation as an early life aversive experience. We have investigated PV expressing interneurons and PNNs in the hippocampus and the RSC of adult male mice, using unbiased stereology. In the CA1, but not in the CA3 region, of the hippocampus, the number of PNNs and PV + PNN+ cells was affected by the drug treatment, and a significant decrease of these parameters was observed in the groups of animals that received MK801. The percentage of PNNs surrounding PV+ cells was significantly decreased after treatment in both hippocampal regions; however, the impact of isolation was observed only in CA1, where isolated animals presented lower percentages. In the RSC, we observed significant effects of isolation, MK801 and the interaction of both interventions on the studied parameters; in the DHM, we observed a significantly lower number of PV+, PNNs, and PV+PNN+cells when compared to control mice. Similar significant decreases were observed for the groups of animals that were just isolated or treated with MK801. To our knowledge, this is the first report on such alterations in the RSC in an animal model combining neurodevelopmental alterations and aversive experiences during infancy/adolescence. These results show the impact of early-life events on different cortical regions, especially on the structure and plasticity of PV+ neurons and their involvement in the emergence of certain psychiatric disorders.

Highlights

Schizophrenia is a complex and multifactorial disease with a lifetime risk of about 1% (Schultz et al, 2007), resulting in dramatic cognitive deficits, behavioral and emotional dysfunctions (Harrison, 1999), usually starting from late adolescence and early adulthood (Cannon and Jones, 1996)
We have previously shown in mice that the combination of these paradigms in a double hit model (DHM) causes changes in anxiety and locomotor behaviors (Castillo-Gómez et al, 2017) and a decrease in prepulse inhibition of the startle reflex (Garcia-Mompo et al, 2020)
We found that the volume, the structure and connectivity of excitatory and inhibitory neurons, and the expression of molecules related to inhibitory transmission and its plasticity were altered in the prefrontal cortex (PFC) and the amygdala (CastilloGómez et al, 2017; Garcia-Mompo et al, 2020)

Summary

Introduction

Schizophrenia is a complex and multifactorial disease with a lifetime risk of about 1% (Schultz et al, 2007), resulting in dramatic cognitive deficits, behavioral and emotional dysfunctions (Harrison, 1999), usually starting from late adolescence and early adulthood (Cannon and Jones, 1996). The complex etiology of schizophrenia is still not fully understood, some predisposing factors have already been recognized (Howes et al, 2004), including early life aversive experiences (Corcoran et al, 2003; Read et al, 2005). Some of the most affected brain regions by these early life adverse events, which are known to be altered in schizophrenia, are the prefrontal cortex (PFC), the amygdala, and the hippocampus (Phillips et al, 2003; McEwen et al, 2016). Different reports have described alterations induced by early life stress in the retrosplenial cortex (RSC; Aksic et al, 2014; Markovic et al, 2014), a region within the posterior neocortical system, interconnected with both cortical and subcortical brain networks (Vogt et al, 2004). The RSC is especially vulnerable to the action of N-methyl-Daspartate receptor (NMDAR) receptor antagonists, which have propsychotic actions and are used frequently in animal models of schizophrenia (Olney et al, 1999)

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