Disrupted striatal neuron inputs and outputs in Huntington's disease

Abstract

Huntington's disease (HD) is a hereditary progressive neurodegenerative disorder caused by a CAG 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 HD 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 HD victims and in genetic mouse models of HD. 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 HD, 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 HD. Later loss of direct pathway striatal projection neurons and their output to the internal pallidal segment account for the severe akinesia seen late in HD. Loss of parvalbuminergic striatal interneurons may contribute to the late dystonia and rigidity.

Alterations in synaptic function and plasticity in Huntington disease

“…Moreover, dopamine activation of D2 receptors on striatal cholinergic interneurons reduces acetylcholine release, effectively reducing inhibition of dSPN activity (Augustin et al, ). In HD models, although cholinergic interneurons survive, acetylcholine release becomes reduced or dysregulated (Reiner and Deng, ). An excess of dopamine could therefore promote further imbalance favoring the direct pathway and, given the role that dopamine signaling appears to play in HD pathogenesis (discussed below), contribute to the selective vulnerability of iSPNs.…”

Single synapse indicators of impaired glutamate clearance derived from fast iGluu imaging of cortical afferents in the striatum of normal and Huntington (Q175) mice

“…Symptomatic HD is characterized by the loss of glutamatergic terminals in the dorsal striatum but it is still not clear whether this disease-related process of synapse pruning is to be attributed to glutamate excitotoxicity (Reiner and Deng, 2018). While the long-term consequences of reduced Glu clearance remain to be clarified, our present experiments provide new evidence suggesting that in symptomatic Q175 mice a significant fraction of PT (~40%) synapses is afflicted by the disease, most likely exhibiting alterations in both uptake and release.…”

“…The striatum as the most affected brain structure in HD (Khakh et al, 2017) is well suited for selective activation of glutamatergic synapses as it lacks intrinsic glutamatergic neurons. Glutamatergic afferents originate in the medial thalamus and the cerebral cortex (see (Reiner and Deng, 2018) for more). Corticostriatal connections are formed by at least two distinct populations of pyramidal neurons, localized in layers 2/3 and 5.…”

mTOR-RhoA signalling impairments in direct striatal projection neurons induce altered behaviours and striatal physiology in mice

“…These are commonly divided into i ) neurodevelopmental, such as some forms of autism (14, 15) and epileptic encephalopathy (16), ii ) psychiatric, including schizophrenia (17) and major depressive disorder (18) and iii ) neurodegenerative disorders, such as Alzheimer’s, Parkinson’s and Huntington’s disease (19–21). Many of these disorders are known to have striatum malfunction as a major factor of their development (22–26).…”