Conditional Knock-out of mGluR5 from Astrocytes during Epilepsy Development Impairs High-Frequency Glutamate Uptake

Astrocyte expression of metabotropic glutamate receptor 5 (mGluR5) is consistently observed in resected tissue from patients with epilepsy and is equally prevalent in animal models of epilepsy. However, little is known about the functional signaling properties or downstream consequences of astrocyte mGluR5 activation during epilepsy development. In the rodent brain, astrocyte mGluR5 expression is developmentally regulated and confined in expression/function to the first weeks of life, with similar observations made in human control tissue. Herein, we demonstrate that mGluR5 expression and function dramatically increase in a mouse model of temporal lobe epilepsy (TLE). Interestingly, in both male and female mice, mGluR5 function persists in the astrocyte throughout the process of epileptogenesis following status epilepticus. However, mGluR5 expression and function is transient in animals that do not develop epilepsy over an equivalent time period, suggesting that patterns of mGluR5 expression may signify continuing epilepsy development or its resolution. We demonstrate that during epileptogenesis, astrocytes re-acquire mGluR5-dependent calcium transients following agonist application or synaptic glutamate release—a feature of astrocyte-neuron communication absent since early development. Finally, we find that the selective and conditional knockout of mGluR5 signaling from astrocytes during epilepsy development slows the rate of glutamate clearance through astrocyte glutamate transporters under high-frequency stimulation conditions, a feature that suggests astrocyte mGluR5 expression during epileptogenesis may recapitulate earlier developmental roles in regulating glutamate transporter function. SIGNIFICANCE STATEMENT In development, astrocyte mGluR5 signaling plays a critical role in regulating structural and functional interactions between astrocytes and neurons at the tripartite synapse. Notably, mGluR5 signaling is a positive regulator of astrocyte glutamate transporter expression and function—an essential component of excitatory signaling regulation in hippocampus. After early development, astrocyte mGluR5 expression is downregulated, but re-emerges in animal models of TLE development and patient epilepsy samples. We explored the hypothesis that astrocyte mGluR5 re-emergence recapitulates earlier developmental roles during TLE acquisition. Our work demonstrates that astrocytes with mGluR5 signaling during TLE development perform faster glutamate uptake in hippocampus, revealing a previously unexplored role for astrocyte mGluR5 signaling in hypersynchronous pathology.