Disrupted striatal neuron inputs and outputs in Huntington's disease

Abstract

<p id="d5121607e205">Huntington's disease ( <span style="fixed-case">HD</span>) is a hereditary progressive neurodegenerative disorder caused by a <span style="fixed-case">CAG</span> repeat expansion in the gene coding for the protein huntingtin, resulting in a pathogenic expansion of the polyglutamine tract in the N‐terminus of this protein. The <span style="fixed-case">HD</span> pathology resulting from the mutation is most prominent in the striatal part of the basal ganglia, and progressive differential dysfunction and loss of striatal projection neurons and interneurons account for the progression of motor deficits seen in this disease. The present review summarizes current understanding regarding the progression in striatal neuron dysfunction and loss, based on studies both in human <span style="fixed-case">HD</span> victims and in genetic mouse models of <span style="fixed-case">HD</span>. We review evidence on early loss of inputs to striatum from cortex and thalamus, which may be the basis of the mild premanifest bradykinesia in <span style="fixed-case">HD</span>, as well as on the subsequent loss of indirect pathway striatal projection neurons and their outputs to the external pallidal segment, which appears to be the basis of the chorea seen in early symptomatic <span style="fixed-case">HD</span>. Later loss of direct pathway striatal projection neurons and their output to the internal pallidal segment account for the severe akinesia seen late in <span style="fixed-case">HD</span>. Loss of parvalbuminergic striatal interneurons may contribute to the late dystonia and rigidity. </p>