Interferon-γ enhances neocortical synaptic inhibition by promoting membrane association and phosphorylation of GABAA receptors in a protein kinase C-dependent manner

Interferon-gamma (IFN-gamma), an important mediator of the antiviral immune response, can also act as a neuromodulator. CNS IFN-gamma levels rise acutely in response to infection and therapeutically applied IFN-gamma provokes CNS related side effects. Moreover, IFN-gamma plays a key role in neurophysiological processes and a variety of chronic neurological and neuropsychiatric conditions. To close the gap between basic research, behavioral implications and clinical applicability, knowledge of the mechanism behind IFN-gamma related changes in brain function is crucial. Here, we studied the underlying mechanism of acutely augmented neocortical inhibition by IFN-gamma (1.000 IU ml(-1)) in layer 5 pyramidal neurons of male Wistar rats. We demonstrate postsynaptic mediation of IFN-gamma augmented inhibition by pressure application of GABA and analysis of paired pulse ratios. IFN-gamma increases membrane presence of GABA(A)R gamma(2), as quantified by cell surface biotinylation and functional synaptic GABA(A)R number, as determined by peak-scaled non-stationary noise analysis. The increase in functional receptor number was comparable to the increase in underlying miniature inhibitory postsynaptic current (mIPSC) amplitudes. Blockage of putative intracellular mediators, namely phosphoinositide 3-kinase and protein kinase C (PKC) by Wortmannin and Calphostin C, respectively, revealed PKC-dependency of the pro-inhibitory IFN-gamma effect. This was corroborated by increased serine phosphorylation of P-serine PKC motifs on GABA(A)R gamma(2) upon IFN-gamma application. GABA(A)R single channel conductance, intracellular chloride levels and GABA(A)R driving force are unlikely to contribute to the effect, as shown by single channel recordings and chloride imaging. The effect of IFN-gamma on mIPSC amplitudes was similar in female and male rats, suggesting a gender-independent mechanism of action. Collectively, these results indicate a novel mechanism for the regulation of inhibition by IFN-gamma, which could impact on neocortical function and therewith behavior.

Automated summary

IFN-gamma plays an important role in the central nervous system, enhancing the regulation of GABA(A)R and impacting neocortical function and behavior.