| Summary: | Multiple neurotransmitter systems have been implicated in the pathophysiology of schizophrenia. In particular, changes in the GABAergic and glutamatergic system could be upstream to changes in the dopamine system, and also responsible for the cognitive and negative symptoms of the disease. This thesis has utilised genetic models of glutamatergic dysfunction, both globally in mice lacking the GluA1 AMPAR subunit (Gria1 KO), and in a circuit specific manner in mice lacking the NR1 NMDAR subunit specifically in parvalbumin (PV) positive interneurons (Grin1?PV). In addition, the chemogenetic DREADD silencer hM4Di was used to transiently and specifically silence PV positive interneurons in vivo. These genetic and chemogenetic manipulations have been used in combination with behavioural assays that could assess schizophrenia-relevant behaviours in rodents. Grin1?PV animals were found to be largely normal when tested for schizophrenia-relevant behavioural abnormalities. However, when Grin1?PV animals were challenged with the NMDAR antagonist MK-801 (commonly used to pharmacologically model glutamatergic dysfunction) there was clear behavioural divergence between Grin1?PV and control animals. In contrast to previous reports, Grin1?PV mice appeared to be sensitised to the effects of MK-801. This has important implications for the understanding of how NMDAR antagonists can induce schizophrenia-relevant behavioural deficits in rodents. Hypofunction of PV interneurons, particularly in the hippocampus, is predicted to underlie schizophrenia-relevant behavioural deficits. To directly test this, hM4Di was expressed in PV interneurons in the dorsal or ventral hippocampus, preferentially in area CA1. Despite the fact that hM4Di was capable of reducing the excitability of PV interneurons in vitro, there was no evidence that silencing of PV interneurons in CA1 in vivo could induce the predicted behavioural deficits. Gria1 KO mice have a well established behavioural phenotype that could be relevant to schizophrenia. A viral-rescue approach was utilised to reintroduce GluA1 preferentially into area CA3 of the hippocampus of Gria1 KO animals. This was sufficient to rescue novelty induced hyperactivity and spatial novelty preference but not spatial working memory in Gria1 KO animals. Recordings of local field potentials (LFP) in the dorsal hippocampus revealed enhanced theta power oscillations in Gria1 KO mice. This elevated theta power was also rescued by GluA1 re-introduction into area CA3 of Gria1 KO mice. Together these experiments question the hypothesis that NMDAR antagonists preferentially exert their effects through NMDARs on PV interneurons. In addition, with respect to schizophrenia-related behavioural deficits, hypofunction of PV interneurons in area CA1 of the hippocampus might not be be as critical as hypofunction of PV interneurons in other circuits. Finally, area CA3 of the hippocampus is implicated as a brain region in which GluA1 expression appears particularly important for some behaviours relevant to schizophrenia.
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