Dysregulation of synaptic proteins, dendritic spine abnormalities and pathological plasticity of synapses as experience-dependent mediators of cognitive and psychiatric symptoms in Huntington's disease.
Huntington's disease (HD) is an autosomal dominant tandem repeat expansion disorder involving cognitive, psychiatric and motor symptoms. The expanded trinucleotide (CAG) repeat leads to an extended polyglutamine tract in the huntingtin protein and a subsequent cascade of molecular and cellular pathogenesis. One of the key features of neuropathology, which has been shown to precede the eventual loss of neurons in the cerebral cortex, striatum and other areas, are changes to synapses, including the dendritic protrusions known as spines. In this review we will focus on synapse and spine pathology in HD, including molecular and experience-dependent aspects of pathogenesis. Dendritic spine pathology has been found in both the human HD brain at post mortem as well as various transgenic and knock-in animal models. These changes may help explain the symptoms in HD, and synaptopathy within the cerebral cortex may be particularly important in mediating the psychiatric and cognitive manifestations of this disease. The earliest stages of synaptic dysfunction in HD, as assayed in various mouse models, appears to involve changes in synaptic proteins and associated physiological abnormalities such as synaptic plasticity deficits. In mouse models, synaptic and cortical plasticity deficits have been directly correlated with the onset of cognitive deficits, implying a causal link. Furthermore, following the discovery that environmental enrichment can delay onset of affective, cognitive and motor deficits in HD transgenic mice, specific synaptic molecules shown to be dysregulated by the polyglutamine-induced toxicity were also found to be beneficially modulated by environmental stimulation. This identifies potential molecular targets for future therapeutic developments to treat this devastating disease.
Centre for Clinical Brain Sciences & Centre for Neuroregeneration, Chancellor's Building, University of Edinburgh, United Kingdom. Electronic address: Jess.N@ed.ac.uk.
J
J
Nithianantharajah
A J
AJ
Hannan
D000818:Animals; D001921:Brain / Q000473:pathology*; D003071:Cognition; D049229:Dendritic Spines / Q000473:pathology*; D004195:Disease Models, Animal; D006801:Humans; D006816:Huntington Disease / Q000473:pathology* / Q000523:psychology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009473:Neuronal Plasticity; D013569:Synapses / Q000473:pathology*
D008565:Membrane Proteins