Article

The corticostriatal pathway in Huntington's disease.

Mental Retardation Research Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA.
Progress in Neurobiology (Impact Factor: 10.3). 05/2007; 81(5-6):253-71. DOI: 10.1016/j.pneurobio.2006.11.001
Source: PubMed

ABSTRACT The corticostriatal pathway provides most of the excitatory glutamatergic input into the striatum and it plays an important role in the development of the phenotype of Huntington's disease (HD). This review summarizes results obtained from genetic HD mouse models concerning various alterations in this pathway. Evidence indicates that dysfunctions of striatal circuits and cortical neurons that make up the corticostriatal pathway occur during the development of the HD phenotype, well before there is significant neuronal cell loss. Morphological changes in the striatum are probably primed initially by alterations in the intrinsic functional properties of striatal medium-sized spiny neurons. Some of these alterations, including increased sensitivity of N-methyl-D-aspartate receptors in subpopulations of neurons, might be constitutively present but ultimately require abnormalities in the corticostriatal inputs for the phenotype to be expressed. Dysfunctions of the corticostriatal pathway are complex and there are multiple changes as demonstrated by significant age-related transient and more chronic interactions with the disease state. There also is growing evidence for changes in cortical microcircuits that interact to induce dysfunctions of the corticostriatal pathway. The conclusions of this review emphasize, first, the general role of neuronal circuits in the expression of the HD phenotype and, second, that both cortical and striatal circuits must be included in attempts to establish a framework for more rational therapeutic strategies in HD. Finally, as changes in cortical and striatal circuitry are complex and in some cases biphasic, therapeutic interventions should be regionally specific and take into account the temporal progression of the phenotype.

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