Overexpression of astrocytic glutamate transporters alleviates hyperexcitability in mouse model of Alzheimer’s Disease

Abstract

AbstractBackgroundAstrocytes are the main cells responsible for clearing glutamate from the synapse; their glutamate transporters quickly and efficiently clear glutamate within the synaptic cleft, preventing neuronal excitotoxicity. In mouse models and human cases of Alzheimer’s Disease (AD), the astrocyte‐specific glutamate transporter (Glt1 in rodents and EAAT2 in humans) is decreased. Our goal is to study the effects of decreased glutamate transporters on synaptic measures of function and plasticity.MethodUsing a 5XFAD mouse model of amyloid pathology, we utilized an adeno‐associated virus (AAV) to over‐express Glt1 in the hippocampus. Electrophysiological field recordings examined the role of astrocyte‐specific glutamate transporters in synaptic plasticity and hyperexcitability. Animals received injections of AAV‐Luciferase (control) in one hippocampus, and AAV‐Glt1a in the contralateral hippocampus. Field recordings were performed to assess excitatory postsynaptic potentials in the hippocampal CA1 stratum radiatum elicited by stimulation of CA3 axons.ResultCompared to control (AAV‐Luciferase), AAV‐Glt1 significantly increased the expression of glutamate transporters in hippocampal tissue. We then compared measures of neuronal hyperexcitability, synaptic strength, and long‐term synaptic potentiation. Results indicate that there is more hyperexcitability in control tissues compared to AAV‐Glt injections, as evident by decreased population spike thresholds.ConclusionOthers have reported hippocampal hyperexcitability may lead to memory impairment; in human cases of AD it is thought to encourage epileptic episodes. By using our AAV‐directed technique to increase glutamate transporters, and thus reduce network hyperexcitability, we will be able to examine how reactive astrocytes and their loss of glutamate transporters contribute to memory or cognition loss. Ongoing studies will do exactly this‐ use a mouse model of AD with and without AAV Glt1 overexpression to determine changes in behavioral cognitive outcome measures that may be attributed to hyperexcitability in neuronal networks.