Interferon-? acutely augments inhibition of neocortical layer 5 pyramidal neurons.

ABSTRACT: BACKGROUND:Interferon-? (IFN-?, a type II IFN) is present in the central nervous system (CNS) under various conditions. Evidence is emerging that, in addition to its immunological role, IFN-? modulates neuronal morphology, function, and development in several brain regions. Previously, we have shown that raising levels of IFN-? (a type I IFN) lead to increased neuronal excitability of neocortical layer 5 pyramidal neurons. Because of shared non-canonical signaling pathways of both cytokines, we hypothesized a similar neocortical role of acutely applied IFN-?. METHODS:We used semi-quantitative RT-PCR, immunoblotting, and immunohistochemistry to analyze neuronal expression of IFN-? receptors and performed whole-cell patch-clamp recordings in layer 5 pyramidal neurons to investigate sub- and suprathreshold excitability, properties of hyperpolarization-activated cyclic nucleotide-gated current (Ih), and inhibitory neurotransmission under the influence of acutely applied IFN-?. RESULTS:We show that IFN-? receptors are present in the membrane of rat's neocortical layer 5 pyramidal neurons. As expected from this and the putative overlap in IFN type I and II alternative signaling pathways, IFN-? diminished Ih, mirroring the effect of type I IFNs, suggesting a likewise activation of protein kinase C (PKC). In contrast, IFN-? did neither alter subthreshold nor suprathreshold neuronal excitability, pointing to augmented inhibitory transmission by IFN-?. Indeed, IFN-? increased electrically evoked inhibitory postsynaptic currents (IPSCs) on neocortical layer 5 pyramidal neurons. Furthermore, amplitudes of spontaneous IPSCs and miniature IPSCs were elevated by IFN-?, whereas their frequency remained unchanged. CONCLUSIONS:The expression of IFN-? receptors on layer 5 neocortical pyramidal neurons together with the acute augmentation of inhibition in the neocortex by direct application of IFN-? highlights an additional interaction between the CNS and immune system. Our results strengthen our understanding of the role of IFN-? in neocortical neurotransmission and emphasize its impact beyond its immunological properties, particularly in the pathogenesis of neuropsychiatric disorders.

SUBMITTER: Janach GMS 

PROVIDER: S-EPMC7035745 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature