Abstract
BackgroundInterferon-γ (IFN-γ, 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-γ modulates neuronal morphology, function, and development in several brain regions. Previously, we have shown that raising levels of IFN-β (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-γ.MethodsWe used semi-quantitative RT-PCR, immunoblotting, and immunohistochemistry to analyze neuronal expression of IFN-γ 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-γ.ResultsWe show that IFN-γ 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-γ diminished Ih, mirroring the effect of type I IFNs, suggesting a likewise activation of protein kinase C (PKC). In contrast, IFN-γ did neither alter subthreshold nor suprathreshold neuronal excitability, pointing to augmented inhibitory transmission by IFN-γ. Indeed, IFN-γ 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-γ, whereas their frequency remained unchanged.ConclusionsThe expression of IFN-γ receptors on layer 5 neocortical pyramidal neurons together with the acute augmentation of inhibition in the neocortex by direct application of IFN-γ highlights an additional interaction between the CNS and immune system. Our results strengthen our understanding of the role of IFN-γ in neocortical neurotransmission and emphasize its impact beyond its immunological properties, particularly in the pathogenesis of neuropsychiatric disorders.
Highlights
Interferon-γ (IFN-γ, a type II IFN) is present in the central nervous system (CNS) under various conditions
IFN-γ receptor (IFN-γR) is expressed in neocortical layer 5 pyramidal neurons IFN-γR expression has been confirmed for several brain regions [24, 29]
Subsequent Western blot studies detected posttranslational expression of the ligand binding receptor α chain (IFN-γRα, known as IFNGR1 or CD119) only in the membrane fractions derived from neocortical tissue (Fig. 1a, b, right)
Summary
Interferon-γ (IFN-γ, a type II IFN) is present in the central nervous system (CNS) under various conditions. We have shown that raising levels of IFN-β (a type I IFN) lead to increased neuronal excitability of neocortical layer 5 pyramidal neurons. Because of shared noncanonical signaling pathways of both cytokines, we hypothesized a similar neocortical role of acutely applied IFN-γ. Interferons (IFN) are antiviral cytokines known for their multifaceted influence on the immune response. Based on their amino acid sequence, three types of IFNs are distinguished: IFN I to III. IFN-γ is the only member of type II IFNs. IFN-γ is the only member of type II IFNs It plays an important role in innate and adaptive immune response. IFN-γ is involved in dendritic remodeling [10] and synaptic
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