P1-112: Alzheimer’s disease-related depletions of calcium-dependent proteins in the dentate gyrus may reflect chronic Aβ-induced increases in neuronal excitability

Abstract

Cognitive deficits in human amyloid precursor protein (hAPP) transgenic mice are tightly linked to the depletion of calcium–dependent proteins in granule cells of the dentate gyrus, and similar molecular alterations have been found in cases with Alzheimer's disease (AD) [PNAS 100: 9572; J. Neurosci. 25: 9686]. Several lines of evidence suggest that these deficits may involve an attenuation of NMDA–dependent signaling pathways that regulate synaptic activity–dependent genes, such as Arc and Fos. Calcium–dependent proteins in granule cells are also decreased in human disorders and mouse models with chronic neuronal hyperexcitability. Here we tested the hypothesis that the depletion of calcium–dependent proteins in the dentate gyrus of hAPP mice is associated with aberrant neuronal excitability. 4– to 6–month–old transgenic mice expressing familial AD–mutant hAPP (line J20) and nontransgenic littermates were first assessed in a battery of behavioral tests. Subsequently, they were challenged by intraperitoneal injection of GABA antagonists to determine their propensity to develop epileptic activity. Behavioral measures and seizure severity were correlated with the levels of calcium–dependent protein levels in the dentate. Compared with nontransgenic controls, hAPP mice were more susceptible to GABA antagonist–induced seizures, although untreated hAPP mice showed no spontaneous seizure activity. The extent of learning and memory deficits of hAPP mice at baseline correlated with seizure severity after injection of the GABA antagonist and with the depletion of calbindin, Arc, and Fos in the dentate gyrus identified postmortem. In nontransgenic mice, glutamate agonists or GABA antagonists caused depletions of calbindin, Arc, and Fos in nontransgenic mice that were qualitatively and quantitatively similar to those observed in untreated hAPP mice. Treatment of hAPP mice with drugs that enhance inhibitory activities prevented some of the Aβ–dependent behavioral deficits. Chronic Aβ–induced increases in neuronal excitability may trigger compensatory mechanisms in the entorhinal–hippocampal network that allow for the survival of granule cells but result in the neuronal depletion of calcium–dependent proteins that are critical for learning and memory. Drugs that block neuronal hyperexcitability and normalize the activity in this network may be of therapeutic benefit in AD.