Early changes in synaptic and intrinsic properties of dentate gyrus granule cells in a mouse model of Alzheimer's disease neuropathology and atypical effects of the cholinergic antagonist atropine.

Abstract

It has been reported that hyperexcitability occurs in a subset of patients with Alzheimers disease (AD) and hyperexcitability could contribute to the disease. Several studies have suggested that the hippocampal dentate gyrus (DG) may be an important area where hyperexcitability occurs. Therefore, we tested the hypothesis that the principal DG cell type, granule cells (GCs), would exhibit changes at the single-cell level which would be consistent with hyperexcitability and might help explain it. We used the Tg2576 mouse, where it has been shown that hyperexcitability is robust at 2-3 months of age. GCs from 2-3-month-old Tg2576 mice were compared to age-matched wild type (WT) mice. Effects of muscarinic cholinergic antagonism were tested because previously we found that Tg2576 mice exhibited hyperexcitability in vivo that was reduced by the muscarinic cholinergic antagonist atropine, counter to the dogma that in AD one needs to boost cholinergic function. The results showed that GCs from Tg2576 mice exhibited increased frequency of spontaneous excitatory postsynaptic potentials/currents (sEPSP/Cs) and reduced frequency of spontaneous inhibitory synaptic events (sIPSCs) relative to WT, increasing the excitation:inhibition (E:I) ratio. There was an inward glutamatergic current that we defined here as a novel synaptic current (nsC) in Tg2576 mice because it was very weak in WT mice. Although not usually measured, intrinsic properties were distinct in Tg2576 GCs relative to WT. In summary, GCs of the Tg2576 mouse exhibit early electrophysiological alterations that are consistent with increased synaptic excitation, reduced inhibition, and muscarinic cholinergic dysregulation. The data support previous suggestions that the DG and cholinergic system contribute to hyperexcitability early in life in AD mouse models. HIGHLIGHTSO_LIGranule cells (GCs) in young Tg2576 mice had abnormal synaptic activity. C_LIO_LIYoung Tg2576 GCs had increased excitatory and reduced inhibitory synaptic activity. C_LIO_LIGC intrinsic properties were altered in young Tg2576 mice. C_LIO_LIMuscarinic cholinergic regulation of GCs was altered in young Tg2576 mice. C_LIO_LIAtropine led to a novel spontaneous inward current that was very strong in Tg2576 GCs. C_LI