Synaptic dysfunction in the perirhinal cortex of the R6/1 mouse model of Huntington's disease

Cummings, Damian Michael (2004). Synaptic dysfunction in the perirhinal cortex of the R6/1 mouse model of Huntington's disease. PhD thesis The Open University.



Huntington's disease (HD) is a fatal brain disorder characterised by a progressive motor, psychiatric and cognitive decline, often manifesting in midlife. Since the identification of the gene responsible for HD and the development of predictive testing, it has become apparent that asymptomatic patients often exhibit early cognitive deficits. In particular, an impairment in recognition memory that is evident prior to the onset of classical symptoms and trank cell death. The perirhinal cortex is believed to be involved in processing aspects of recognition memory, specifically the discrimination between novel and familiar cues. Evidence suggests that activity-dependent decrements in neuronal activity within the perirhinal region could underlie this cognitive process and that the synaptic mechanism may be one of long-term depression (LTD).

In the R6/1 mouse model of HD, synaptic plasticity is progressively altered in the perirhinal cortex in vitro. LTD expression is enhanced at one month, but then declines and is absent by 7 months of age. Dopamine is shown here to be a neuromodulator at normal perirhinal cortical synapses. Fluorescent immunohistochemical techniques are used to demonstrate altered dopamine receptor expression in the R6/1 perirhinal cortex that correlates with the aberrant synaptic plasticity. By exposing normal mouse slices to a D2 dopamine receptor antagonist, it is possible to recapitulate the R6/1 perirhinal synaptic phenotype. Importantly, the alteration of synaptic fiinction and loss of LTD in R6/1 mice can be restored by applying an agonist of dopamine receptors to brain slices.

These data suggest that impaired perirhinal LTD may contribute to poor recognition memory and that the defect is at the level of the dopaminergic system. Moreover, dopaminergic therapy, targeted to the cortex, may be beneficial in HD.

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