AW Lasek1, M Galan-Llario1, H Chen1, E Legge1, J Almeida1, L Carvalho1, CM Erikson2, R Vlkolinsky2, M Bajo2, and M Roberto2

STAT3 is a transcription factor activated downstream of cytokine, chemokine, and growth factor receptor stimulation. It plays an important role in the innate immune response by promoting astrocyte reactivity and neuroinflammation in response to tissue injury. STAT3 is activated in several brain regions following chronic ethanol exposure in mice, rats and humans. To determine if astrocyte-expressed STAT3 regulates ethanol consumption, we generated conditional astrocyte Stat3 knockout (Stat3aKO) mice. Male, but not female, Stat3aKO consumed less ethanol than controls. To determine potential mechanisms contributing to decreased ethanol consumption in the Stat3aKO mice, we recorded glutamate receptor-mediated spontaneous excitatory post-synaptic currents (sEPSCs) in prelimbic pyramidal neurons in male Stat3aKO and control mice. We found a significant increase in the mean baseline sEPSC amplitude, but not frequency, in Stat3aKO mice. As astrocytes are involved in uptake of synaptic glutamate, we hypothesized that STAT3 might regulate the expression of glutamate transporters and measured transcript levels of Slc1a2, Slc1a3, Slc7a11, and Slc17a8 in Stat3aKO and control mice. Slc1a2 and Slc17a8 were significantly decreased in both male and female Stat3aKO mice, although the magnitude of the decrease was greater in males. These results suggest impaired glutamate clearance in male Stat3aKO mice, and that STAT3 in astrocytes promotes binge drinking. In conclusion, this study links neuroimmune signaling in astrocytes to cortical excitatory neurotransmission and ethanol consumption.

1Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA, 2Department of Translational Medicine, The Scripps Research Institute, La Jolla, CA, USA

Funding support: NIAAA U01AA020912 and R01AA027231 to AWL; U01AA013498 and P60AA006420 to MR; T32 AA007456 to CME.