Astrocyte-mediated tonic inhibition in a mouse model of Lewy body dementia

Lewy body dementia (LBD) is the second most common form of dementia after Alzheimer’s disease (AD), affecting over 1.4 million Americans. The causes of LBD remain largely unknown, and there is currently no cure. This application aims to explore the mechanisms that underlie the genetic link between LBD and mutations in GBA1, the gene that encodes the lysosomal enzyme glucocerebrosidase (GCase). Homozygous recessive mutations in GBA1 cause Gaucher disease, the most common lysosomal storage disorder, which is often associated with parkinsonism and cognitive impairment. Heterozygous GBA1 mutations, however, represent the strongest genetic risk factor for both LBD and Parkinson’s disease (PD), and are linked to more severe cognitive impairment and more rapid cognitive decline. Despite the role of GBA1 mutations in promoting α-synuclein (αSyn) pathology, little is known about how these mutations contribute to the pathophysiology of LBD. Using an astrocyte specific Gba1 conditional knockout (Gba1CKO) mouse model, we have found that astrocyte Gba1 deficiency induces hippocampus dependent mild cognitive impairment. By crossing Gba1CKO mice with the well- characterized Thy1-αSyn (Line 61) mouse model of LBD, which overexpresses human wild-type αSyn, we provide evidence that astrocyte Gba1 deficiency exacerbates LBD-related αSyn accumulation, cognitive impairment and motor symptoms. Gba1CKO mice further demonstrate an increase in levels of hippocampal astrocyte GABA transporter GAT-3, a reduction in extrasynaptic GABAAR-mediated tonic inhibition in CA1 pyramidal neurons, and a defect in autophagy-lysosome degradation. Based on these preliminary findings, we hypothesize that GBA1 deficiency disrupts astrocyte GAT-3-mediated GABA uptake and tonic inhibition, leading to increased neuronal excitability and more severe αSyn accumulation during the prodromal phase of LBD. Three specific aims are proposed: Aim 1 will determine whether GAT-3 upregulation contributes to impaired tonic inhibition and neuronal hyperexcitability in Gba1CKO mice; Aim 2 will assess whether GAT-3 upregulation is caused by autophagy-lysosome dysfunction in Gba1CKO mice; Aim 3 will examine whether impaired tonic inhibition exacerbates neuronal hyperexcitability and αSyn pathology in the Gba1CKO:Thy1-αSyn LBD model mice. The successful completion of this project will reveal a novel astrocyte-mediated mechanism for LBD pathogenesis and inform the development of more effective therapies. Project Number: 1R21AG098840-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Guomei Tang | Institution: COLUMBIA UNIVERSITY HEALTH SCIENCES, NEW YORK, NY | Award Amount: $452,375 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 AN-C (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11301238