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

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.

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

“…Based on this, there are extensive reviews which focus on the role of perineuronal nets in schizophrenia [ 290 , 291 , 292 , 293 , 294 ]. Nevertheless, a currently published study utilized a double-hit model with a perinatal injection of the NMDAR antagonist MK801, combined with a post-weaning social isolation as an early-life stress event [ 295 ]. 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 ].…”

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

“…Examining the papers as a group, however, suggests that stress may have variable effects on PNNs depending on the duration of time after stress exposure. Several studies show decreased PNNs immediately after stress (Ueno et al, 2017;Pesarico et al, 2019;Gildawie et al, 2020Gildawie et al, , 2021Koskinen et al, 2020;Yu et al, 2020;Klimczak et al, 2021), and a rebound increase in PNNs as time passes following stress cessation (Dimatelis et al, 2013;Riga et al, 2017;Murthy et al, 2019;Koskinen et al, 2020;Gildawie et al, 2021). Although some findings do not fit with this summary (Page and Coutellier, 2018;Richardson et al, 2021), the majority of studies suggest a stress-induced trajectory involving first suppression followed by an overshooting rebound, similar to what has been observed for reelin signaling (Zhang et al, 2013).…”

Chronic hM3Dq-DREADD mediated chemogenetic activation of parvalbumin-positive inhibitory interneurons in postnatal life alters anxiety and despair-like behavior in adulthood in a task and sex-dependent manner

“…Luo et al ., 2020). However, it is noteworthy that several environmental, pharmacological and genetic perturbation models of neurodevelopmental disorders are reported to impact PV-positive interneuron structure and function across multiple networks (Smith-Hicks, 2013; Goodwill et al ., 2018; Todorović et al ., 2019; Soares et al ., 2020; Aksic et al ., 2021; Bueno-Fernandez et al ., 2021; Klimczak et al ., 2021; Mukhopadhyay et al ., 2021; Woodward and Coutellier, 2021). In this regard, our approach to chemogenetically manipulate PV-positive interneurons during postnatal development across diverse circuits bears relevance to both models of early adversity and neurodevelopmental disorders, which impact PV-positive interneurons across several limbic brain regions (Ruden et al ., 2021).…”

“…PV expression shows up within the first two postnatal weeks following birth in rodents (Seto-Ohshima et al, 1990;de Lecea et al, 1995;Fishell, 2007;Marín, 2012;Bartolini, et al, 2013;Wong et al, 2018) and matures through the early juvenile period, marked by an increase in both intensity of PV expression and the number of PV-positive interneurons, as well as the formation and strengthening of PV interneuron synapses through perineuronal net (PNN) deposition, which is associated with the eventual closure of critical windows (Favuzzi et al, 2017;Bucher et al, 2021). Indeed, it has been hypothesized that PV-positive interneuron dysregulation during these developmental windows (Marín, 2012;Bartolini et al, 2013;Canetta et al, 2016;Santiago et al, 2018;Murthy et al, 2019;Gildawie et al, 2020;Ohta et al, 2020;Gildawie et al, 2021;Guadagno et al, 2021;Klimczak et al, 2021;Nakamura et al, 2021) be one of the key pathophysiological mechanisms contributing to the neurodevelopmental origins of multiple psychiatric disorders (Ferguson and Gao, 2018;Ruden et al, 2021), such as major depression (Fogaça and Duman, 2019;Spijker et al, 2020), bipolar disorder (Konradi et al, 2011), autism (Contractor et al, 2021) and schizophrenia (Lewis et al, 2012;Dienel and Lewis, 2019).…”