The role of depolarizing GABA in Alzheimer's disease

Northwestern University At Chicago, Evanston IL

Investigators

Abstract

Summary Alzheimer’s disease (AD) represents one of the most urgent unmet medical needs of our time. This devastating condition has an enormous impact on the lives of patients, their families and society as a whole. Despite huge research investments, the treatment options remain very few, their efficacy limited, and the occurrence of side effects troubling. This is largely due to the fact that the cellular mechanisms of cognitive impairment in AD and in other dementias remain unclear. The prefrontal cortex (PFC) is critical for higher brain function and goal- oriented behavior. Numerous studies have identified a clear link between cortical electrical oscillations and cognitive tasks, and aberrant oscillations have been observed in multiple cognitive disorders, including AD. Because GABAergic inhibition is critical for oscillations, much attention has been given to the role of excitatory-inhibitory (E/I) feedback in network dynamics, and altered E/I balance is suggested as critical in many neurological disorders characterized by cognitive impairment. Despite the centrality of E/I imbalance in numerous brain disorders, the underlying cellular mechanisms are mostly unknown. E/I imbalance may be due to abnormalities in GABAergic (inhibitory) and/or glutamatergic (excitatory) signaling. Numerous studies suggest that GABA signaling dysfunction underlies reduced brain oscillations and working memory deficits. Accordingly, a recent meta-analysis has identified GABA signaling as particularly vulnerable and a potential therapeutic target in AD. A peculiar biophysical feature of the GABAA current is that the value of its reversal potential is close to the resting membrane potential of most neurons, and thus relatively small variations in the current reversal potential may shift the current effect from hyperpolarizing to depolarizing. The value of the GABAA current reversal potential is mainly regulated by the activity of NKCC1 (SLC12A2) and KCC2 (SLC12A5), two chloride-cation co-transporters that import and export chloride ions, respectively. Numerous recent papers show that depolarizing GABAA current, which is the norm in early development, is present in the adult PFC in diverse brain disorders and may underlie the altered E/I balance in these conditions. Here we hypothesize that depolarizing GABAA current in the PFC of adult animals is a cause of E/I imbalance and cognitive impairment in AD. Accordingly, our preliminary data suggest that restoration of GABAA inhibitory function in the mPFC of an AD mouse model rescues cognitive performance. To test our hypothesis, we will use perforated-patch recordings from acute slices to measure the GABAA current reversal potential, quantitative in- situ hybridization to quantify the expression of NKCC1 and KCC2 RNA in the PFC of APP-Ki NLGF, 5xFAD and control mice, and behavioral assays to determine the effect of pharmacological inhibition of cortical NKCC1 on working and recollection memory in AD mice. Besides the advancement in understanding basic biological mechanisms of cognitive impairment, our experiments may have immediate translational potential, as there are FDA-approved NKCC1 blockers that could rapidly be tested in clinical trials.