Pathophysiology of a mouse model of X-linked mental retardation

Gill, Kalbinder Kaur (2013). Pathophysiology of a mouse model of X-linked mental retardation. University of Birmingham. Ph.D.

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Abstract

Mental retardation (MR) affects 23% of the population; those due to X linked mutations commonly result in moderate to severe MR. The OPHN1 gene (Ophn1 in mice) has been implicated in X linked mental retardation (XLMR) and encodes the RhoGAP protein, oligophrenin 1. Loss of function mutations alter Rho GTPase dependent signalling pathways and result in altered actin cytoskeleton dynamics which are important in dendritic spine structure, the site of neurotransmission. Here, using electrophysiological recordings combined with intracellular staining techniques and dendritic morphological analysis, I characterise synaptic (dys)function in neocortical and hippocampal neurons from the Ophn1 mouse model of MR. This study demonstrates an excitatory synaptic deficit in neocortical neurons combined with region specific changes in dendritic spine morphology. Inhibitory transmission was normal in both neocortical and hippocampal neurons. Kainate induced gamma oscillations were unaltered whereas spontaneous oscillations were reduced which lead to changes in synaptic function in CA3. Morphometric analysis showed ventriculomegaly in Ophn1 deficient mice that was associated with reduced cortical thickness. This study shows the loss of several previously reported phenotypes, including, altered inhibitory transmission, gamma oscillations and vesicle dynamics. Their loss, but preservation of morphological deficits, suggests that the model may be susceptible to genetic drift.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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