Understanding the role of the NMDA receptor subunit, GluN2D, in mediating NMDA receptor antagonist-induced behavioral disruptions in male and female mice.

Noncompetitive NMDA receptor (NMDAR) antagonists like phencyclidine (PCP) and ketamine cause psychosis-like symptoms in healthy humans, exacerbate schizophrenia symptoms in people with the disorder, and disrupt a range of schizophrenia-relevant behaviors in rodents, including hyperlocomotion. This is negated in mice lacking the GluN2D subunit of the NMDAR, suggesting the GluN2D subunit mediates the hyperlocomotor effects of these drugs. However, the role of GluN2D in mediating other schizophrenia-relevant NMDAR antagonist-induced behavioral disturbances, and in both sexes, is unclear. This study aimed to investigate the role of the GluN2D subunit in mediating schizophrenia-relevant behaviors induced by a range of NMDA receptor antagonists. Using both male and female GluN2D knockout (KO) mice, we examined the effects of the NMDAR antagonist's PCP, the S-ketamine enantiomer (S-ket), and the ketamine metabolite R-norketamine (R-norket) on locomotor activity, anxiety-related behavior, and recognition and short-term spatial memory. GluN2D-KO mice showed a blunted locomotor response to R-norket, S-ket, and PCP, a phenotype present in both sexes. GluN2D-KO mice of both sexes showed an anxious phenotype and S-ket, R-norket, and PCP showed anxiolytic effects that were dependent on sex and genotype. S-ket disrupted spatial recognition memory in females and novel object recognition memory in both sexes, independent of genotype. This datum identifies a role for the GluN2D subunit in sex-specific effects of NMDAR antagonists and on the differential effects of the R- and S-ket enantiomers.

Brain-Derived Neurotrophic Factor Val66Met polymorphism interacts with adolescent stress to alter hippocampal interneuron density and dendritic morphology in mice.

Brain-derived neurotrophic factor (BDNF) plays essential roles in GABAergic interneuron development. The common BDNF val66met polymorphism, leads to decreased activity-dependent release of BDNF. The current study used a humanized mouse model of the BDNF val66met polymorphism to determine how reduced activity-dependent release of BDNF, both on its own, and in combination with chronic adolescent stress hormone, impact hippocampal GABAergic interneuron cell density and dendrite morphology. Male and female Val/Val and Met/Met mice were exposed to corticosterone (CORT) or placebo in their drinking water from weeks 6-8, before brains were perfuse-fixed at 15 weeks. Cell density and dendrite morphology of immunofluorescent labelled inhibitory interneurons; somatostatin, parvalbumin and calretinin in the CA1, and 3 and dentate gyrus (DG) across the dorsal (DHP) and ventral hippocampus (VHP) were assessed by confocal z-stack imaging, and IMARIS dendritic mapping software. Mice with the Met/Met genotype showed significantly lower somatostatin cell density compared to Val/Val controls in the DHP, and altered somatostatin interneuron dendrite morphology including branch depth, and spine density. Parvalbumin-positive interneurons were unchanged between genotype groups, however BDNF val66met genotype influenced the dendritic volume, branch level and spine density of parvalbumin interneurons differentially across hippocampal subregions. Contrary to this, no such effects were observed for calretinin-positive interneurons. Adolescent exposure to CORT treatment also significantly altered somatostatin and parvalbumin dendrite branch level and the combined effect of Met/Met genotype and CORT treatment significantly reduced somatostatin and parvalbumin dendrite spine density. In sum, the BDNFVal66Met polymorphism significantly alters somatostatin and parvalbumin-positive interneuron cell development and dendrite morphology. Additionally, we also report a compounding effect of the Met/Met genotype and chronic adolescent CORT treatment on dendrite spine density, indicating that adolescence is a sensitive period of risk for Val66Met polymorphism carriers.

Sex-specific spatial memory deficits in mice with a conditional TrkB deletion on parvalbumin interneurons.

Schizophrenia is a debilitating disorder characterised by three main symptom categories: positive, negative and cognitive. Cognitive symptoms emerge first, and currently do not have appropriate treatments, despite being a strong predictor of the severity and progress of the illness. Cognitive deficits are strongly associated with the dysfunction of GABAergic parvalbumin interneurons (PV-IN). PV-IN are supported by Brain-Derived Neurotrophic Factor (BDNF) via its receptor Tropomyosin-related Kinase B (TrkB). The main aim of this study was to investigate the cognitive and affective consequences of disrupted BDNF-TrkB signalling at PV-IN. We crossed PV-Cre mice with heterozygous TrkB floxed mice (PV-Cre:Fl+/-) to knock-down TrkB receptors on PV-IN. Male and female mice underwent a battery of tests including: Y-Maze, Cheeseboard Maze, Elevated Plus Maze, and Locomotor activity. Co-expression of PV and TrkB in the hippocampus was assessed by fluorescent immunohistochemistry and detailed stereology. Sex-specific spatial memory impairments were found in the Y-Maze. Only male PV-Cre:Fl+/- mice showed no preference for the novel arm. Furthermore, there was a male specific genotype difference in memory retrieval in the Cheeseboard Maze. Male PV-Cre:Fl+/- mice were more preservative in their learning than male PV-Cre control mice. Overall, the evidence from this study suggests that sex had a developmental influence on this constitutive model. Male spatial memory was altered by the disruption to BDNF-TrkB signalling at PV-IN. This aligns with males showing more severe cognitive dysfunction in schizophrenia.

Sex differences in animal models of schizophrenia shed light on the underlying pathophysiology.

Sex differences in schizophrenia are apparent in almost all features of the illness, from incidence and mean age of onset to symptomatology, course of illness and response to pharmacological treatments. Understanding how men and women with schizophrenia differ provides significant clues into the pathophysiology of the disorder. Animal models are powerful tools when dissecting the molecular biology which underlies behavioural disturbances, and allow structured comparisons of biological sex differences without the social environmental gender influence that so often confounds human sex comparison studies. This review will provide a summary of sex differences described in developmental, genetic and drug-induced animal models of schizophrenia and will link sex-specific molecular and behavioural phenotypes of these models in an attempt to unravel the role that sex plays in the pathophysiology of schizophrenia. Both sex and stress hormones interact to shape the developing brain and behaviour and animal models of schizophrenia that include both sexes provide significant insight into the complexities of these interactions and can direct toward novel therapeutic strategies.