GABAReceptor signaling in CA1 Pyramidal Cells is not Regulated by Aging in the APP/PS1 Mouse Model of Amyloid Pathology.

Abstract

Dementia-causing diseases, including Alzheimer's disease (AD), are one of the greatest health concerns facing the aging world population. A key feature of AD is excessive accumulation of amyloid-beta, leading to synapse and cell loss in brain structures, such as the hippocampus. This neurodegeneration is preceded by impaired neuron function, notably reduced synaptic inhibition. Metabotropic GABAreceptors (GABARs) may be modulated by amyloid precursor protein (APP) and are reported to be progressively lost from neuronal membranes of hippocampal pyramidal neurons. However, it remains unknown whether functional GABAR-mediated signaling changes over aging and whether or not pharmacological intervention can prevent receptor loss. In this study, we combine electrophysiological and biochemical analysis of hippocampal neurons in the Amyloid Precursor Protein/Presenilin-1 (APP/PS1) mouse model of AD from acute brain slices and organotypic slice cultures prepared from male and female mice to determine if functional GABARs are lost and the effect of pharmacological modulation. Overall, we found that GABAR expression decreased with age, independent of genotype, with no evidence for postsynaptic GABAR loss in CA1 pyramidal cells at any age. We did observe a genotype-dependent reorganization of postsynaptic GABAR-mediated IPSCs, which was independent of age. Presynaptic GABAR-mediated inhibition was impaired in APP/PS1 mice, also independent of age. We observed that chronic GABAR modulation differentially regulated function but was independent of genotype. Overall, our data show that functional GABAR signaling is altered in APP/PS1 mice, independent of age, increasing our understanding of amyloidopathy-induced dysfunction.