Abstract
Medium spiny neurons (MSNs) comprise over 90% of cells in the striatum. In vivo MSNs display coherent burst firing cell assembly activity patterns, even though isolated MSNs do not burst fire intrinsically. This activity is important for the learning and execution of action sequences and is characteristically dysregulated in Huntington's Disease (HD). However, how dysregulation is caused by the various neural pathologies affecting MSNs in HD is unknown. Previous modeling work using simple cell models has shown that cell assembly activity patterns can emerge as a result of MSN inhibitory network interactions. Here, by directly estimating MSN network model parameters from single unit spiking data, we show that a network composed of much more physiologically detailed MSNs provides an excellent quantitative fit to wild type (WT) mouse spiking data, but only when network parameters are appropriate for the striatum. We find the WT MSN network is situated in a regime close to a transition from stable to strongly fluctuating network dynamics. This regime facilitates the generation of low-dimensional slowly varying coherent activity patterns and confers high sensitivity to variations in cortical driving. By re-estimating the model on HD spiking data we discover network parameter modifications are consistent across three very different types of HD mutant mouse models (YAC128, Q175, R6/2). In striking agreement with the known pathophysiology we find feedforward excitatory drive is reduced in HD compared to WT mice, while recurrent inhibition also shows phenotype dependency. We show that these modifications shift the HD MSN network to a sub-optimal regime where higher dimensional incoherent rapidly fluctuating activity predominates. Our results provide insight into a diverse range of experimental findings in HD, including cognitive and motor symptoms, and may suggest new avenues for treatment.
Highlights
Huntington’s Disease (HD) is an inherited condition caused by an abnormal expansion of CAG trinucleotide repeats in the mutant huntingtin gene (The Huntington’s Disease Collaborative Research Group, 1993)
The age of disease onset is roughly related to the length of abnormally expanded CAG repeats in the mutant huntingtin gene, but how this produces HD is not well understood
HD is found to be primarily associated with pathology of medium spiny neurons (MSNs) in the striatum, the main input stage of the basal ganglia
Summary
Huntington’s Disease (HD) is an inherited condition caused by an abnormal expansion of CAG trinucleotide repeats in the mutant huntingtin (mHTT) gene (The Huntington’s Disease Collaborative Research Group, 1993). Striatal medium spiny neuron (MSN) dysfunction is a prominent finding and may be a pathophysiological cause of HD symptoms. Neuronal and synaptic dysfunction precedes cell death by many years in humans [14,15,16] and occurs before, or even in the absence of, cell death in HD animal models [17,18,19,20]. Similar alterations of striatal synaptic activity have been demonstrated in multiple different HD mouse models [23]. Progressive changes in spontaneous corticostriatal excitatory synaptic activity [24,25,26,27] have been associated with pre- and postsynaptic alterations including reductions in synaptic proteins, loss of dendritic spines, and loss of synapses [1, 9, 24, 28,29,30,31]. A progressive disconnection between cortex and striatum seems to be a general characteristic of HD
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