Endocannabinoid-Specific Impairment in Synaptic Plasticity in Striatum of Huntington's Disease Mouse Model

Abstract

Huntington's disease (HD) is an inherited neurodegenerative disease affecting predominantly striatum and cortex that results in motor and cognitive disorders. Before a motor phenotype, animal models of HD show aberrant cortical-striatal glutamate signaling. Here, we tested synaptic plasticity of cortical excitatory synapses onto striatal spiny projection neurons (SPNs) early in the YAC128 mouse model of HD. High-frequency stimulation-induced long-term depression, mediated by the endocannabinoid anandamide and cannabinoid receptor 1 (CB1), was significantly attenuated in male and female YAC128 SPNs. Indirect pathway SPNs, which are more vulnerable in HD, were most affected. Our experiments show metabotropic glutamate receptor and endocannabinoid 2-arachidonoylglycerol-dependent plasticity, as well as direct CB1 activation by agonists, was similar in YAC128 and FVB/N wild-type SPNs suggesting that presynaptic CB1 is functioning normally. These results are consistent with a specific impairment in postsynaptic anandamide synthesis in YAC128 SPN. Strikingly, although suppression of degradation of anandamide was not effective, elevating 2-arachidonoylglycerol levels restored long-term depression in YAC128 striatal neurons. Together, these results have potential implications for neuroprotection and ameliorating early cognitive and motor deficits in HD. Huntington's disease (HD) is an inherited neurodegenerative disease with no cure. Recent studies find impairment of the endocannabinoid system in animal models but the functional implication for synaptic plasticity in HD remains unclear. Sepers et al. show a selective deficit in synaptic plasticity mediated by the endocannabinoid anandamide, but not 2-arachidonoylglycerol in a mouse model of HD. The deficit is rescued by selectively elevating levels of 2-arachidonoylglycerol produced on-demand. This mechanism could be targeted in the development of future therapeutics for HD.

BDNF Controls Bidirectional Endocannabinoid Plasticity at Corticostriatal Synapses

“…In neurodegenerative diseases, such as Huntington disease, (Strand et al 2007;Zuccato and Cattaneo 2009;Park 2018;Yu et al 2018) and neurodevelopmental disorders (Autry and Monteggia 2012;Baydyuk and Xu 2014;Deinhardt and Chao 2014), BDNF release is strongly diminished. In the light of our results, this reduction of BDNF account for the reduction or the loss of synaptic plasticity, as observed in Huntington disease rodent models (Kolodziejczyk et al 2014;Plotkin et al 2014;Sepers et al 2018). On the opposite, BDNF levels are increased in maladaptive disorders such as ethanol or cocaine addiction (Jeanblanc et al 2009;Im et al 2010;Lu et al 2010;Bahi and Dreyer 2013) or neurogenetic disorders, such as DYT1 dystonia (Maltese et al, 2018).…”

Deficit in Motor Skill Consolidation-Dependent Synaptic Plasticity at Motor Cortex to Dorsolateral Striatum Synapses in a Mouse Model of Huntington’s Disease

“…Indeed, deletion of striatal NMDAR abolished striatal LTP and impaired learning (Dang et al, 2006). Furthermore, R6/2 mice show less NMDAdependent LTP in the striatum compared to WT control (Kung et al, 2007) while deficit in endocannabinoid-dependent LTD was observed in the YAC128 mice (Sepers et al, 2018).…”

Dysfunctional striatal dopamine signaling in Huntington's disease

“…Impaired cortico‐striatal plasticity has been reported in HD mice (Kung, Hassam, Morton, & Jones, ; Plotkin et al, ; Sepers et al, ). At early stages, both YAC128 and Q175/FDN iSPNs (Southwell et al, ) show impaired high‐frequency stimulation (HFS)‐induced LTD (Sepers et al, ), a presynaptically expressed form of LTD that results from postsynaptic activation of group I metabotropic glutamate receptors, D2 receptors, L‐type Ca2+ channels and calcium‐induced calcium release from Ryanodine receptors to synthesize anandamide. Anandamide binds to presynaptic CB1 receptors, decreasing glutamate release from cortical terminals (Lovinger, ).…”