Functional Differences Between Direct and Indirect Striatal Output Pathways in Huntington's Disease

Abstract

There is morphological evidence for differential alterations in striatal medium-sized spiny neurons (MSNs) giving rise to the direct and indirect output pathways in Huntington's disease (HD). MSNs of the indirect pathway appear to be particularly vulnerable and markers for these neurons are lost early in postmortem brains and in genetic mouse models. In contrast, MSNs of the direct pathway appear to be relatively spared in the early stages. Because of the great morphological and electrophysiological similarities between MSNs of these pathways, until recently it was difficult to tease apart their functional alterations in HD models. The recent use of the enhanced green fluorescent protein gene as a reporter to identify dopamine D1 (direct pathway) and D2 (indirect pathway) receptor-expressing MSNs has made it possible to examine synaptic function in each pathway. The outcomes of such studies demonstrate significant time-dependent changes in the balance of excitatory and inhibitory inputs to both direct and indirect pathway MSNs in HD and emphasize early increases in both excitatory and inhibitory inputs to direct pathway MSNs. There also is a strong influence of alterations in dopamine modulation that possibly cause some of the changes in excitatory and inhibitory synaptic transmission in the HD models. These changes will markedly alter the output structures, the GPi and the SNr. In the future, the use of combined optogenetics with identified neurons in each pathway will help unravel the next set of questions about how the output nuclei are affected in HD.

Disrupted striatal neuron inputs and outputs in Huntington's disease

“…119,[248][249][250][251][252] Moreover, SPNs show electrophysiological signs of cortical disconnection in R6/2, Q175, or YAC128 mice at symptomatic ages at which SPNs do not yet show loss. 100,135,136,251,253 The corticostriatal input arises from 2 neuron types, an intratelencephalically projecting (IT) type residing predominantly in layer III and upper layer V, and a pyramidal tract (PT) type located primarily in lower layer V. [254][255][256][257][258][259][260][261][262] We and other investigators have found in rats and monkeys that PT-type corticostriatal neurons preferentially contact striatal neurons projecting to GPe with larger terminals, while IT-type cortical neurons preferentially target striatal neurons projecting to GPi or SNr with smaller terminals (Figure 12). [263][264][265][266] In our study in 12-month-old Q140 mice, the loss of corticostriatal terminals occurred selectively for smaller terminals, suggesting they might be IT-type terminals and preferentially lost from direct pathway type striatal neurons.…”

“…121,248,251,270,271 The dSPNs in particular show early enhanced and later reduced corticostriatal excitation. 253,270,272 The reduced corticostriatal excitation appears to reflect the loss of corticostriatal input rather than reduced striatal excitability, because dSPNs remain more depolarized at rest and have elevated membrane input resistances. 248,252,273 The preferential loss of cortical input to dSPNs we observed is of interest in light of the possibility that the loss is neuroprotective.…”

Corticostriatal network dysfunction in Huntington's disease: Deficits in neural processing, glutamate transport, and ascorbate release

“…41 In fact, a shift in MSN excitability could alter the dynamics of behavior-related neuronal processing throughout basal ganglia circuitry. 42,43 Accordingly, Cayzac et al 44 reported a change in the ability of MSNs to process learning and task-related information in premotor-symptomatic R6/1 mice, another truncated model of HD but with later symptom onset owing to a smaller number (~110) of CAG repeats.…”

Striatal cholinergic interneurons and cortico‐striatal synaptic plasticity in health and disease

“…Huntington's disease is an inherited neurodegenerative disease characterized by a selective loss of MSNs in the striatum. 149,150 Huntington's disease is caused by a mutation in the Huntingtin gene encoding the Huntingtin protein and is characterized by movement disorders (eg, involuntary choreiform movements) and behavioral and cognitive deficits. 37,151 Even though no specific degeneration of the striatal cholinergic interneurons has been described in HD, [152][153][154] studies in HD transgenic mice have reported an abnormally low release of ACh in the striatum, 2,155 pointing out a role of these interneurons in the pathophysiology of the disease.…”