LRRK2 G2019S disrupts GABAergic signaling and shifts excitatory/inhibitory balance in the striatum

Abstract

The excitatory/inhibitory (E/I) balance within neural circuits is essential for proper brain function, and its disruption is a hallmark of several neurodegenerative diseases. In Parkinsons disease (PD), widespread alterations in the basal ganglia circuitry lead to an E/I imbalance in the striatum, contributing to excitotoxicity. Leucine-rich repeat kinase 2 (LRRK2) has recently emerged as a key contributor to both familial and sporadic forms of PD, with the pathogenic Gly2019Ser (G2019S) mutation representing one of the most frequently observed variants. This mutation is known to exacerbate excitotoxicity by impairing glutamate reuptake mechanisms, particularly through dysregulation of EAAT2 activity and its membrane localization. In contrast, the role of LRRK2 in GABAergic transmission remains poorly understood. Here, we reveal a clear modulation of inhibitory signaling by LRRK2 through a comprehensive approach combining mouse striatal slices and Xenopus laevis oocytes. Our results demonstrate, for the first time, that LRRK2 G2019S induces a significant reduction in GABA-evoked current amplitudes. Moreover, we identified an altered distribution of receptor isoforms in pathological tissue, affecting both tonic and phasic GABA currents. Specifically, synaptic GABAA receptors containing the {gamma}2 subunit were functionally modulated by LRRK2 G2019S. The reduced availability of gephyrin in the presence of the G2019S variant may impair the gephyrin-GABAA receptor complex, leading to decreased receptor surface expression and further shifting the glutamate/GABA current ratio toward excitatory dominance. This is supported by the increased activity of AMPA and NMDA receptors observed in the pathological striatum. Overall, our findings highlight a previously underappreciated role of LRRK2 G2019S in impairing GABAergic transmission and disrupting the E/I balance. These insights point to novel circuit-level mechanisms underlying LRRK2-linked PD and suggest new avenues for the development of disease-modifying therapies targeting inhibitory dysfunction. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=76 SRC="FIGDIR/small/684189v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1b685b3org.highwire.dtl.DTLVardef@3ea39org.highwire.dtl.DTLVardef@1064a58org.highwire.dtl.DTLVardef@1fb0304_HPS_FORMAT_FIGEXP M_FIG C_FIG The LRRK2 G2019S mutation contributes to excitatory/inhibitory imbalance by reducing GABA-evoked currents. Specifically, it is associated with diminished phasic GABAergic transmission and enhanced tonic inhibition, suggesting an altered subcellular distribution of GABAA receptor subtypes.