An expansion of glutamine repeats in the N-terminal domain of the huntingtin protein leads to Huntington's disease (HD), a neurodegenerative condition characterized by the presence of involuntary movements, dementia, and psychiatric disturbances. Evaluation of postmortem HD tissue indicates that the most prominent cell loss occurs in cerebral cortex and striatum, forebrain regions in which cortical pyramidal neurons (CPNs) and striatal medium spiny neurons (MSNs) are the most affected. Subsequent evidence obtained from HD patients and especially from transgenic mouse models of HD indicates that long before neuronal death, patterns of communication between CPNs and MSNs become dysfunctional. In fact, electrophysiological signaling in transgenic HD mice is altered even before the appearance of the HD behavioral phenotype, suggesting that dysfunctional cortical input to the striatum sets the stage for the emergence of HD neurological signs. Striatal MSNs, moreover, project back to cortex via multi-synaptic connections, allowing for even further disruptions in cortical processing. An effective therapeutic strategy for HD, therefore, may lie in understanding the synaptic mechanisms by which it dysregulates the corticostriatal system. Here, we review literature evaluating the molecular, morphological, and physiological alterations in the cerebral cortex, a key component of brain circuitry controlling motor behavior, as they occur in both patients and transgenic HD models.
Huntington’s Disease (HD) is a fatally inherited neurodegenerative disorder caused by an expanded glutamine repeat in the N-terminal region of the huntingtin (HTT) protein. The result is a progressively worsening triad of cognitive, emotional, and motor alterations that typically begin in adulthood and end in death 10-20 years later. Autopsy of HD patients indicates massive cell loss in the striatum and its main source of input, the cerebral cortex. Further studies of HD patients and transgenic animal models of HD indicate that corticostriatal neuronal processing is altered long before neuronal death takes place. In fact, altered neuronal function appears to be the primary driver of the HD behavioral phenotype, and dysregulation of glutamate, the excitatory amino acid released by corticostriatal afferents, is believed to play a critical role. Although mutant HTT interferes with the operation of multiple proteins related to glutamate transmission, consistent evidence links the expression of mutant HTT with reduced activity of glutamate transporter 1 (rodent GLT1 or human EAAT2), the astrocytic protein responsible for the bulk of glutamate uptake. Here, we review corticostriatal dysfunction in HD and focus on GLT1 and its expression in astrocytes as a possible therapeutic target.
Abnormal electrophysiological activity in the striatum, which receives dense innervation from the cerebral cortex, is believed to set the stage for the behavioral phenotype observed in Huntington's disease (HD), a neurodegenerative condition caused by mutation of the huntingtin (mhtt) protein. However, cortical involvement is far from clear. To determine whether abnormal striatal processing can be explained by mhtt alone (cell-autonomous model) or by mhtt in the corticostriatal projection cell-cell interaction model, we used BACHD/Emx1-Cre (BE) mice, a conditional HD model in which full-length mhtt is genetically reduced in cortical output neurons, including those that project to the striatum. Animals were assessed beginning at 20 weeks of age for at least the next 40 weeks, a range over which presymptomatic BACHD mice become symptomatic. Both open-field and nest-building behavior deteriorated progressively in BACHD mice relative to both BE and wild-type (WT) mice. Neuronal activity patterns in the dorsal striatum, which receives input from the primary motor cortex (M1), followed a similar age progression because BACHD activity changed more rapidly than either BE or WT mice. However, in the M1, BE neuronal activity differed significantly from both WT and BACHD. Although abnormal cortical activity in BE mice likely reflects input from mhtt-expressing afferents, including cortical interneurons, improvements in BE striatal activity and behavior suggest a critical role for mhtt in cortical output neurons in shaping the onset and progression of striatal dysfunction.
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