Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Neuroscience

Supervisor

Rajakumar, Nagalingam

2nd Supervisor

Allman, Brian L.

Co-Supervisor

Abstract

Schizophrenia is a psychotic disorder consisting of positive, negative, and cognitive symptoms. While patients currently have access to treatments for the positive and negative symptoms, no satisfactory treatment exists to alleviate the cognitive deficits, which cause severe impairments to the quality of life of patients and their families. Although the mechanisms underlying the cognitive deficits of schizophrenia are not clear, a decreased dendritic spine density on layer 3 pyramidal neurons in the dorsolateral prefrontal cortex has been strongly implicated. Generally, the adult brain is not permissive to the formation of new dendritic spines. Recently, an immune receptor called paired immunoglobulin-like receptor B (PirB) has been identified to play an active role in inhibiting dendritic spine growth in the adult brain. The current thesis infused PirB blocker into the prefrontal cortex of a rat model that recapitulates several neuroanatomical changes and behavioral deficits associated with schizophrenia, and then analyzed dendritic spine densities using Golgi-Cox method and immunohistochemical labelling of Neurabin-2. The results showed a significant increase in spine density in Golgi-Cox impregnated neurons, and increased Neurabin-2 labelling following infusions of PirB blocker compared to vehicle infusions. These results provide a promising first step in the development of a novel treatment for the cognitive deficits of schizophrenia.

Summary for Lay Audience

Schizophrenia is a severe psychiatric disorder characterized by positive, negative, and cognitive symptoms. The cognitive symptoms in schizophrenia consist of deficits in working memory, attention and executive function, and can have negative impacts on the everyday lives of people with this disorder. The cognitive symptoms have been shown to be associated with degenerative changes in neuronal dendrites, particularly loss of dendritic spines; microscopic protrusions on the surface that receive excitatory connections to neurons of the cerebral cortex. As the adult brain does not support regeneration of dendritic spines, this poses a significant impediment to restoring lost connections. The current study was conducted with the aim of increasing the number of dendritic spines in the prefrontal cortex of adult rats that show many of the common symptoms seen in schizophrenia. This was achieved by blocking the function of a regulatory protein called PirB, which had recently been shown to inhibit the growth of new dendritic spines in the visual cortex. The current thesis used two staining techniques: the Golgi-Cox method, which allows for the quantification of individual dendritic spines in a small number of randomly labelled cells; and immunohistochemistry, which allows for a broader scale observation of dendritic spines in a larger population of cells. Our findings show for the first time that the number of dendritic spines can be significantly increased in adult rats by infusing a PirB blocker into the prefrontal cortex, the cortical area implicated in the degeneration of schizophrenia. Ultimately, the work in this thesis provides insight into how PirB regulates dendritic spine growth in the prefrontal cortex, and how to reverse the loss of dendritic spines in this brain region. Considering a loss of dendritic spines in the prefrontal cortex mediates certain cognitive deficits of schizophrenia, these current findings provide a possible first step in developing a novel treatment for these cognitive deficits.

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