Selective induction of astrocytic gliosis generates deficits in neuronal inhibition

Abstract

Reactive astrocytosis develops in many neurologic diseases including epilepsy. Astrocytotic contributions to pathophysiology are poorly understood. Studies examining this are confounded by comorbidities accompanying reactive astrocytosis. We found that high-titer AAV-eGFP astrocyte transduction induced reactive astrocytosis without altering the intrinsic properties or anatomy of neighboring neurons. We used selective astrocytosis induction to examine consequences on synaptic transmission in mouse CA1 pyramidal neurons. Neurons near eGFP-labeled reactive astrocytes exhibited reduction in inhibitory, but not excitatory synaptic currents. This IPSC erosion resulted from failure of the astrocytic glutamate-glutamine cycle. Reactive astrocytes downregulated expression of glutamine synthetase. Blockade of this enzyme normally induces rapid synaptic GABA depletion. In astrocytotic regions, residual inhibition lost sensitivity to glutamine synthetase blockade, while exogenous glutamine administration enhanced IPSCs. Astrocytosis-mediated deficits in inhibition triggered glutamine-reversible hyperexcitability in hippocampal circuits. Reactive astrocytosis may thus generate local synaptic perturbations, leading to broader functional deficits associated with neurologic disease.