Semester

Fall

Date of Graduation

2003

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Physiology, Pharmacology & Neuroscience

Committee Chair

Jia Luo.

Abstract

The development of the cerebellar cortex is dependent on orchestrated cell-cell, cell-matrix interactions, as well as intrinsic genetic programs. Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade ECM molecules and are involved in neuronal migration, process extension, and synaptic plasticity. The current study investigated (1) the developmental expression and activity of MMP-2 and MMP-9, and (2) the effect of blocking the activity of MMP-2 and MMP-9 by a specific inhibitor on the histogenesis of the cerebellar cortex. Cerebella were collected from rat pups every three days starting at postnatal day 3 (P3) until P25---a period equivalent to the third gestational trimester in humans. Temporal analysis of MMP activity by gelatinase assay showed that both the active and latent forms were present in the developing cerebellum. The mRNA analysis by real-time quantitative PCR indicated that the expression pattern of MMP-2 and MMP-9 mRNA agreed with their gelatinase activity. In situ zymography was localized in the EGL, the PCL, and IGL. The EGL, Bergamnn glial fibers, and the PCL showed immunoreactivity for MMP-2, whereas MMP-9 immunoreactivity was detected only in PC and the EGL. Exposure of organotypic slices to a specific MMP-2/MMP-9 inhibitor (1.6, 3.2 or 6.4 muM) altered the activity of MMP-2 and 9 and caused a significant increase in the thickness of the EGL, and a decrease in migrating granule neurons in the molecular layer. Our study suggests that MMP-2 and MMP-9 play a role in the postnatal cerebellar histogenesis.

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