Effect of an astrocyte calcium exporter on orbitofrontal cortex neuron excitability, astrocyte-synaptic interaction, and alcohol consumption

Previous electrophysiology studies show that acute ethanol inhibits firing of orbitofrontal (OFC) cortex neurons while chronic intermittent ethanol (CIE) exposure increases firing accompanied by enhanced ethanol drinking. The acute ethanol inhibition of OFC neuronal firing is mediated by inhibitory glycine receptors and is reduced by expressing a plasma membrane calcium ATPase (PMCA) in OFC astrocytes. In this study, we tested the effects of astrocyte PMCA on CIE-induced increases in excitability and alcohol consumption and the physical interaction between OFC astrocytes and neurons. CIE increased neuronal firing in male mice as compared to Air controls while PMCA itself increased firing in Air control male mice. In contrast, PMCA reduced CIE-mediated hyperexcitability of firing in females. CIE did not affect OFC astrocyte size in control or PMCA male mice but increased astrocyte size in female mice. Similar to spiking, PMCA and CIE both increased the number of GluA1 containing synapses within the vicinity of virally labeled astrocytes in male mice but had differential effects in females. The astrocytic interaction with GluA1 labeled synapses was not affected by CIE treatment in male or female control mice, but there was a treatment-dependent effect of PMCA in male mice. CIE increased alcohol consumption in control but not PMCA male mice and had no effect on drinking in female mice. Lastly, OFC astrocyte PMCA expression had no effect on behavioral measures of locomotion, anxiety, spontaneous alternation, or spatial memory. These findings reveal important sex-dependent differences in the physiological, structural and behavioral actions of OFC astrocytes.