GABAB receptor blockade in the dentate gyrus restores glutamatergic synaptic plasticity and hippocampus dependent memory in an AD-like rat model.

Synaptic dysfunction driven by glutamate-mediated excitotoxicity is a hallmark of hippocampus-dependent memory impairment in Alzheimer's disease (AD). Although GABAergic signaling is known to regulate excitatory/inhibitory (E/I) balance, the precise molecular mechanisms by which GABA and its receptors modulate glutamatergic synaptic plasticity remains incompletely understood. Here, we investigated the role of GABA and its receptors in the dentate gyrus (DG) of a streptozotocin (STZ) induced rat model with sporadic AD (SAD)-like features. sAD rats exhibited intact emotional and motor functions but showed marked impairments in novel object recognition, Y-maze, and Morris water maze (MWM) performance. In vivo microdialysis combined with HPLC during MWM training revealed decreased GABA levels and selective upregulation of GABAB receptor (GABABR) expression, but not GABAAR, expression in the DG. Administration of the GABABR antagonist 2-hydroxysaclofen improved hippocampal memory performance, reduced glutamate accumulation, and restored the key excitatory synaptic markers, including vGlut1 and PSD-95. Moreover, co-immunoprecipitation and molecular docking identified a specific interaction between GABABR and CaMKII. GABABR blockade enhanced CaMKII phosphorylation and activated downstream effectors, including p-CREB and BDNF, indicating re-engagement of plasticity-related signaling. These findings demonstrate that GABABR upregulation in the DG impairs glutamatergic synaptic plasticity and memory function in sAD like rats, likely via direct suppression of the CaMKII/CREB/BDNF pathway. Targeting GABABR may thus offer a promising strategy to restore E/I balance and cognitive performance in a sAD-like rat model.