ABSTRACT
Huntington's disease (HD) is initially characterized by an inability to suppress unwanted movements, a deficit attributable to impaired synaptic activation of striatal indirect pathway spiny projection neurons (iSPNs). To better understand the mechanisms underlying this deficit, striatal neurons in ex vivo brain slices from mouse genetic models of HD were studied using electrophysiological, optical and biochemical approaches. Distal dendrites of iSPNs from symptomatic HD mice were hypoexcitable, a change that was attributable to increased association of dendritic Kv4 potassium channels with auxiliary KChIP subunits. This association was negatively modulated by TrkB receptor signaling. Dendritic excitability of HD iSPNs was rescued by knocking-down expression of Kv4 channels, by disrupting KChIP binding, by restoring TrkB receptor signaling or by lowering mutant-Htt (mHtt) levels with a zinc finger protein. Collectively, these studies demonstrate that mHtt induces reversible alterations in the dendritic excitability of iSPNs that could contribute to the motor symptoms of HD.
Subject(s)
Corpus Striatum/pathology , Huntingtin Protein/metabolism , Huntington Disease/pathology , Huntington Disease/physiopathology , Mutant Proteins/metabolism , Neurons/metabolism , Shal Potassium Channels/metabolism , Animals , Disease Models, Animal , Huntingtin Protein/genetics , Mice , Mutant Proteins/geneticsABSTRACT
Experience-driven plasticity of glutamatergic synapses on striatal spiny projection neurons (SPNs) is thought to be essential to goal-directed behavior and habit formation. One major form of striatal plasticity, long-term depression (LTD), has long appeared to be expressed only pre-synaptically. Contrary to this view, nitric oxide (NO) generated by striatal interneurons was found to induce a post-synaptically expressed form of LTD at SPN glutamatergic synapses. This form of LTD was dependent on signaling through guanylyl cyclase and protein kinase G, both of which are abundantly expressed by SPNs. NO-LTD was unaffected by local synaptic activity or antagonism of endocannabinoid (eCb) and dopamine receptors, all of which modulate canonical, pre-synaptic LTD. Moreover, NO signaling disrupted induction of this canonical LTD by inhibiting dendritic Ca(2+) channels regulating eCb synthesis. These results establish an interneuron-dependent, heterosynaptic form of post-synaptic LTD that could act to promote stability of the striatal network during learning.
