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Cale, Jennifer (2023) Characterisation of GABAergic interneurons in a dual-hit neurodevelopmental model for schizophrenia. MRes thesis, University of Nottingham.

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Abstract

Schizophrenia is a debilitating mental illness distinguished by positive, negative, and cognitive symptoms. Pathogenesis begins in early neurodevelopment and leads to excitatory-inhibitory imbalance that is poorly managed by current treatments. Preclinical models used to understand the disease and evaluate novel therapeutics should therefore consider GABAergic deficits. One approach to improve preclinical models' face, construct, and predictive validity incorporates dual neurodevelopmental ‘hits’. For example, ‘PCP-Iso’ rats that undergo neonatal administration of phencyclidine, to disrupt the development of glutamatergic circuitry, and then post-weaning isolation, to mimic adolescent social stress, exhibit more significant behavioural deficits than either of the single hit models. PCP-Iso may also have better predictive validity than their single-hit counterparts.

A previous finding with the same cohort of PCP-Iso rats used in this study had fewer calbindin-positive GABA interneurons in the hippocampus. The current study expanded on these previous findings and investigated changes to additional populations of GABAergic interneurons, specifically parvalbumin, somatostatin, calbindin, and Iba-1-positive cells in subregions of the frontal cortex and hippocampus. Animal models of schizophrenia and post-mortem human studies have reported increased inflammatory elements such as elevated cytokines and microglial activation. As a result, microglial activation states were also investigated in subregions of the hippocampus as expressed by Iba-1-positive cells.

A cohort of 41 male Lister-hooded rats received saline (1ml/kg s.c.) or PCP (10mg/kg) before rearing in groups or isolation. They underwent novel object discrimination three times before brains were collected for free-floating immunohistochemistry on 60μm coronal sections. Images were obtained from consistently placed regions of interest in the frontal cortex and hippocampus for each biomarker except calbindin, which only the frontal cortex was used due to hippocampal findings being published previously. Cell counts and intensity of immunoreactivity were determined with ImageJ. Microglia activation states were determined through manual examination of Iba-1-positive cells visible in images obtained during immunohistochemistry protocol.

Immunohistochemical findings in the frontal cortex of single-hit and dual-hit rats showed similar reductions of parvalbumin immunoreactivity, with wider deficits seen in PCP-Iso of select subregions of the frontal cortex. This study aims to enhance the field of animal models of schizophrenia and further characterise the face and predictive validity of the dual-hit model approach.

Item Type:	Thesis (University of Nottingham only) (MRes)
Supervisors:	King, Madeleine Farr, Tracy
Keywords:	GABA interneurons, schizophrenia
Subjects:	R Medicine > RC Internal medicine W Medicine and related subjects (NLM Classification) > WM Psychiatry
Faculties/Schools:	UK Campuses > Faculty of Medicine and Health Sciences > School of Life Sciences
Item ID:	71952
Depositing User:	Cale, Jennifer
Date Deposited:	31 Jul 2023 04:40
Last Modified:	31 Jul 2023 04:40
URI:	https://eprints.nottingham.ac.uk/id/eprint/71952

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