Tonic mGluR5/CB1‐dependent suppression of inhibition as a pathophysiological hallmark in the striatum of mice carrying a mutant form of huntingtin

Key points • In neurodegenerative diseases, the afflicted brain provides both an important object of study and an opportunity to characterize a given cellular interaction from a pathophysiological perspective. • This dual approach is particularly advantageous when human disease is based on a monogenetic defect and an appropriate animal model becomes available for detailed investigation, as in case of Z_Q175_KI, a new knock-in mouse expressing a mutant form of murine huntingtin. • Our results challenge the current viewpoint that GABAergic transmission is enhanced in the striatum in Huntington's disease. Quantal analysis in combination with high-frequency stimulation and paired-pulse tests revealed that synaptic GABA release is in fact tonically suppressed, resulting in disinhibition of striatal output activity. • The underlying mechanism involves a retrograde endocannabinoid signalling pathway linking postsynaptic metabotropic glutamate type 5 receptors with presynaptic cannabinoid type 1 receptors and GABA release. • The results help us to understand why pathological elevation of extracellular glutamate levels depresses synaptic inhibition. Abstract  Changes in the activity of striatal output neurons (SONs) have been implicated in the pathogenesis of Huntington's disease (HD). In this inherited polyglutamine disorder, accumulation of intracellular toxins causes a variety of deficits, including synaptic dysfunction, but it is still unclear to what extent striatal GABA release is afflicted as well. Two murine HD models were used, a recently created knock-in mouse (Z_Q175_KI) and an established model of HD (R6/2). In sagittal slices with relatively well-preserved glutamatergic connections throughout the basal ganglia, we have characterized the following: (i) the excitability of SONs; (ii) their spontaneous action potential-dependent GABAergic synaptic activity; (iii) the capacity of exogenous GABA to inhibit spontaneous action potential generation; and (iv) the properties of GABAergic unitary evoked responses (eIPSCs) in response to intrastriatal minimal stimulation at low and high frequency. The HD SONs exhibited enhanced intrisic excitability and higher levels of GABAergic spontaneous activity without presenting evidence for homeostatic upregulation of endogenous or exogenous GABA actions. Unitary eIPSC amplitudes were reduced, with a clear deficit in the probability of release, as indicated by a higher paired-pulse ratio, failure rate and coefficient of variation. In conditions of high-frequency activation, GABAergic connections of HD SONs were prone to asynchronous release and delayed IPSC generation at the expense of synchronized release. Both in wild-type and in HD SONs, GABA was inhibitory. Our results support the conclusion that the enhanced spontaneous synaptic activity in the HD striatum reflects disinhibition. Pharmacological tests identified the HD-related tonic suppression of synaptic inhibition as a glutamate- and endocannabinoid-dependent process.