Synaptic Plasticity And Cognitive Function

Evidence to date suggests that the earliest alteration of neuronal function in mouse models of HD is augmentation of striatal NMDAR function or signaling, to which changes in dopamine signaling may contribute. However, altered NMDAR signaling is not restricted to the striatum. The hippocampus is known to be critical to the formation of episodic memory and, as part of the hippocampo-fronto-striatal pathway, is involved in higher cognitive tasks such as goal-directed behavior and executive function (reviewed in ref. 82). Activity-dependent alterations in synaptic efficacy, such as LTP and long-term depression (LTD), are widely believed to underlie information storage and processing in the brain and may be the best models for cellular substrates of learning and memory (reviewed in ref. 83). Moreover, NMDARs are critical to the induction of many of these modifications. Hippocampal function has been assessed in transgenic30,84 and knock-in17 models of HD, and in each study NMDAR-dependent LTP was altered. In addition, the most conspicuous alteration in R6/2 plasticity is the expression of NMDAR-dependent LTD in adult mice, which is entirely absent in controls30. In all three models, altered plasticity occurs prior to onset of an overt phenotype, and in R6/2 at a time at which hippocampal-dependent learning is impaired27,30. Recent investigations have characterized hippocampal plasticity in R6/1 mice, and following a period of near-normal development, aberrant LTD (mediated by NR2B-containing NMDARs) becomes apparent, long before the onset of an overt phenotype (A. Milnerwood, in press) and prior to reported motor and cognitive and cognitive deficits85.

Cognitive deficits occur early in both HD patients and mouse models, and it seems likely that the mechanisms that underlie aberrant synaptic plasticity and cellular dysfunction in mouse models may contribute to early cognitive deficits in the human condition. Such dysfunction may, therefore, be the basis of many cognitive and behavioral manifestations of HD. Furthermore the mechanisms responsible for such early changes may directly link to later severe dysfunction that ultimately leads to gross cell death.

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