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

Abstract

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 Abbreviations ACSF, artificial cerebrospinal fluid; AIDA, (RS)-1-aminoindan-1,5-dicarboxylic acid; aIPSCs; asynchronous inhibitory postsynaptic currents; AP, action potential; APV, DL-2-amino-5-phosphonopentanoic acid; ...

Increased Metabotropic Glutamate Receptor 5 Signaling Underlies Obsessive-Compulsive Disorder-like Behavioral and Striatal Circuit Abnormalities in Mice

“…Although this finding is ostensibly at odds with the increased striatal firing rates observed in Sapap3 KO mice in vivo (4), mGluR5 signaling affects numerous cellular properties and cell types within the striatal microcircuit, making it difficult to predict its integrated effect on SPN firing rates. For example, in SPNs, mGluR5 signaling potentiates N -methyl-D-aspartate–type glutamate receptor currents (29), disinhibits gamma-aminobutyric acidergic synapses (30), increases intrinsic excitability (31), and mediates corticostriatal synaptic long-term depression (32). Moreover, two key striatal interneuron types that influence SPN activity—fast-spiking and cholinergic interneurons—are also modulated by mGluR5 (33,34).…”

“…In Sapap3 KO mice, mGluR5-mediated increases in SPN activity could arise through a number of local circuit mechanisms, including, but not limited to, increased SPN intrinsic excitability (31) and endocannabinoid-mediated suppression of inhibitory synaptic tone (30,59). Importantly, given how any single isolated feature may fail to accurately predict the net circuit output, we show here the utility of an integrated measure of striatal output in that it accurately reflects the in vivo state (4) and can be used to identify therapies that act locally to normalize circuit output (Figure 3).…”

Reduced tonic inhibition in striatal output neurons from Huntington mice due to loss of astrocytic GABA release through GAT-3

“…Striatal slices of WT and HD origin exhibit AP-dependent spontaneous activity (Dvorzhak et al, 2013). It is therefore not surprising that a major part of I Tonic(GABA) depended on AP-mediated synaptic release of GABA.…”

Selective expression of mutant huntingtin during development recapitulates characteristic features of Huntington’s disease

“…Alterations in excitatory-inhibitory (E-I) balance can also deregulate corticostriatal plasticity (46). Changes in inhibitory (47,48) and excitatory (14,17) inputs to different striatal neurons (MSN-D1 and MSN-D2, fast-spiking interneurons, and persistent low-threshold interneurons) have been observed in BACHD (at both 2 and 12 mo of age) (47) and other mouse models of HD, thereby suggesting another mechanism to explain the alterations in corticostriatal plasticity. These defects in E-I balance may be established during development, given the fact that associated synaptic alterations are present very early in HD mouse models.…”