Hippocampal Girk-Dependent Signaling In Cognitive Function And Alzheimer’S Disease

Abstract

Many neurological disorders derive from, or can be attributed to the disruptions in neuronal plasticity. The GABAB receptor (GABABR) mediates slow inhibitory neurotransmission in the central nervous system and plays a crucial role in neuronal plasticity underlying learning and memory. The signaling via the receptor and the regulation of receptor signaling is one fundamental process contributing to the balance between excitatory and inhibitory signaling that mediates neuronal plasticity. GABABR can signal through a G protein-gated inwardly rectifying K+ (GIRK) channel in most neurons to directly and promptly regulate cell excitability. My thesis work focuses on how neuronal GIRK-dependent signaling (Chapter I) in the hippocampus (HPC) – a crucial region in learning and memory – is regulated by GABABR and other inhibitory G protein-coupled receptors (GPCRs) as well as their regulators (Chapter II), is involved in HPC-related cognitive deficits (Chapter III), and is maladapted in Alzheimer’s Disease (AD), a cognitive disorder and neurodegenerative disease showing severe atrophy in the HPC (Chapter IV). I use mice as my primary experimental model. My work concentrates on the excitatory HPC neurons in vitro and dorsal CA1 pyramidal neurons in vivo. Sex is considered as a biological variant in Chapter III-V. The discussion in Chapter V provides more insights into the sex differences observed in previous chapters.