GABA(B) Receptor signaling in CA1 Pyramidal Cells is not Regulated by Aging in the APP/PS1 Mouse Model of Amyloid Pathology.

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 GABA(B) receptors (GABA(B)Rs) 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 GABA(B)R-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 GABA(B)Rs are lost and the effect of pharmacological modulation. Overall, we found that GABA(B)R expression decreased with age, independent of genotype, with no evidence for postsynaptic GABA(B)R loss in CA1 pyramidal cells at any age. We did observe a genotype-dependent reorganization of postsynaptic GABA(B)R-mediated IPSCs, which was independent of age. Presynaptic GABA(B)R-mediated inhibition was impaired in APP/PS1 mice, also independent of age. We observed that chronic GABA(B)R modulation differentially regulated function but was independent of genotype. Overall, our data show that functional GABA(B)R signaling is altered in APP/PS1 mice, independent of age, increasing our understanding of amyloidopathy-induced dysfunction.