Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Neuroscience

Supervisor

Rajakumar, Nagalingam

2nd Supervisor

Inoue, Wataru

Joint Supervisor

Abstract

During early brain development, the subplate relays thalamocortical afferents. Lesions to the subplate have been implicated in developmental abnormalities of cortical GABAergic circuits. This thesis examined the effects of subplate lesions in the prefrontal cortex of rats on the expression of GABA markers (parvalbumin and GAD67) and GABA synapse maturation [potassium-chloride cotransporter (KCC2) and sodium-potassium- chloride cotransporter (NKCC1)] with relevance to the characterization of a rat model for schizophrenia. Lesions were made on postnatal day 1 (P1). Lesioned and control rats were sacrificed between P5 and P90 and immunolabelled for parvalbumin, GAD67, KCC2, and NKCC1. We found decreased parvalbumin expression in lesioned animals, validating our subplate lesion model in impaired interneuron development. GAD67, KCC2, and NKCC1 levels were unchanged at all timepoints studied compared to control. Despite this, decreased parvalbumin expression may alter cortical E/I balance, as previously seen in behavioral abnormalities of this animal model.

Summary for Lay Audience

During early brain development, the transient subplate layer of the brain relays information from the thalamus to the cerebral cortex to guide the cortex in proper maturation. Previously, studies have shown that damage to the subplate layer of the visual cortex early during development results in abnormal levels of the KCC2 protein, which prevented the maturation of inhibitory neurotransmitter signaling in the visual cortex. On the other hand, damage to the subplate of the prefrontal cortex resulted in decreased levels of parvalbumin, a calcium-binding protein critical for inhibitory neuronal function, as well as behavioral abnormalities reminiscent of human schizophrenia. As schizophrenia has been proposed to be a neurodevelopmental disorder exhibiting abnormal inhibitory neurotransmitter signaling in the prefrontal cortex, we sought to damage the subplate layer of the prefrontal cortex of day 1-old rats. Using fluorescence techniques to detect protein levels in brain sections of subplate-damaged and unaffected (control) rats, we found that subplate-damaged rats exhibited lower levels of parvalbumin in the prefrontal cortex as expected, but KCC2 remained unchanged when compared to control animals. Further, KCC2 partner protein NKCC1, and GAD67, the main enzyme responsible for synthesizing the brain’s inhibitory neurotransmitter, was unchanged. Despite a lack of change in KCC2, NKCC1, and GAD67, the change in parvalbumin protein levels of the prefrontal cortex may cause abnormalities in the subplate-damaged brain, reflected in abnormal behavior of prefrontal subplate-damaged rats. Thus, the subplate plays a significant role in cortical development, and prefrontal subplate-damaged rats may serve as a potential animal model for the study of abnormal inhibitory signaling seen in schizophrenia.

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