Objective: To determine whether parameters of synaptic and extrasynaptic GABAergic inhibition of striatal projection neurons are altered in presymptomatic BACHD mice.

Background: One attractive early hypothesis of HD pathogenesis was that of a GABA deficiency disorder, with hopes for a substitution therapy similar to levodopa for PD. While this turned out to be a drastic oversimplification, direct and indirect pathway striatal projection neurons (SPNs) nevertheless require GABAergic inhibition as protection from excitotoxicity via extensive cortical glutamatergic inputs. Mutant huntingtin impairs receptor trafficking and surface expression, leading to reduced surface GABAA receptors. Reduced tonic GABA currents have been described in rapidly symptomatic R6/2 and Q175 mouse models, likely contributing to striatal neurodegeneration. The BACHD model employed here resembles the disease course in humans more closely, with late onset and slow progression of motor symptoms. This allows a longitudinal observation of SPN GABAergic transmission in HD.

Method: Brain slice preparations of transgenic BACHD, asymptomatic Q31, and wild type FvB mice between 4 and 12 months of age were used for voltage clamp recordings of IPSCs, EPSCs and tonic GABA currents of striatal GFP-tagged D1-SPNs and D2-SPNs.

Results: Tonic GABA currents were significantly reduced in D1- and D2-SPNs of 4 month old presymptomatic BACHD versus control mice of the same age (Ctrl 4M: 30.93±2.73 pA; BACHD 4M: 21.64±1.90 pA; p=0.0074). In contrast, parameters of phasic, synaptic GABAergic transmission of SPNs (IPSC amplitudes and frequency) did not differ between presymptomatic BACHD and control mice. Reduced SPN tonic GABA currents in BACHD persisted into symptomatic disease stages up to 12 months of age.

Conclusion: Reduced SPN tonic GABA currents possibly contribute to the selective vulnerability of these neurons. Our findings suggest that these changes precede loss of neurons and disease onset. Ways of enhancing tonic GABAergic transmission in HD, via direct positive receptor modulation or GABA reuptake blockers, might be explored to counter excitotoxicity and delay striatal neurodegeneration.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/changes-in-gabaergic-transmission-of-striatal-neurons-in-presymptomatic-huntingtons-disease/