Interferon-γ potentiates GABAA receptor-mediated inhibitory currents in rat hippocampal CA1 pyramidal neurons

Abstract

A B S T R A C TThe neural transmission and plasticity can be differentially modulated by various elements of the immune system. Interferon-γ (IFN-γ) is a "pro-inflammatory" cytokine mainly produced by T lymphocytes, activates its corresponding receptor and plays important roles under both homeostatic and inflammatory conditions. However, the impact of IFN-γ on the γ-aminobutyric acid (GABA)-mediated currents in the hippocampus, a major brain region involved in the cognitive function, has not been investigated. Here we detected abundant expression of both IFN-γ receptor subunit gene transcripts (Ifngr1 and Ifngr2) in the rat hippocampus by quantitative PCR. In addition, we pre-incubated rat hippocampal slices with IFN-γ (100 ng/ml) and recorded GABA-activated spontaneous and miniature postsynaptic inhibitory currents (sIPSCs and mIPSCs) and tonic currents in hippocampal CA1 pyramidal neurons by the whole-cell patch-clamp method. The pre-incubation with IFN-γ increased the frequency but not the mean amplitude, rise time or decay time of both sIPSCs and mIPSCs in hippocampal CA1 pyramidal neurons, suggesting a presynaptic effect of IFN-γ. Moreover, the GABAactivated tonic currents were enhanced by IFN-γ. In conclusion, the potentiation of GABAergic currents in hippocampal neurons by IFN-γ may contribute to the disturbed neuronal excitability and cognitive dysfunction during neuroinflammation.

Interferon-γ acutely augments inhibition of neocortical layer 5 pyramidal neurons

“…In line with our findings of an augmented inhibition, layer 1 interneurons respond to meningeal IFN-γ release and increase tonic inhibition in layer 2 projection neurons [36]. Further support of our findings comes from other brain regions such as the hippocampus, where IFN-γ augmented synaptic inhibition as shown in the brain slices of late juvenile rats by an increase in frequency of spontaneous and miniature IPSCs [37] or in culture at peak synaptogenesis by increased spontaneous IPSC frequency and miniature IPSC amplitude [23], both at later time points, i.e., at hours to days after IFN-γ exposure. The latter authors linked their findings to increased neuronal activity, an interaction that recently has been deciphered [38].…”

Interferon-γ augments GABA release in the developing neocortex via nitric oxide synthase/soluble guanylate cyclase and constrains network activity

“…In particular, IFN-γ augments GABA (γ-amino-butyric acid)ergic currents in the developed rat neocortex (Janach et al, 2020) by increasing synaptic GABA A channel number in a protein kinase C (PKC)dependent manner (Janach et al, 2022). In line with this, IFN-γ augments GABAergic currents in the hippocampus (Brask et al, 2004;Flood et al, 2019).…”

Unique aspects of IFN‐γ/STAT1 signaling in neurons

“…Extending IFN‐γ exposure to 4 weeks reduced AMPA clustering in cultured neurons and ultimately decreased activity, offering another example of how different variables can dramatically alter the neuronal response to IFN‐γ. Using a lower concentration (100 U/mL) than the studies listed above, a 3 h exposure of IFN‐γ increased the frequency of spontaneous postsynaptic currents (sIPSCs) and tonic inhibition in rat hippocampal CA1 pyramidal neurons 74 . Tonic inhibition, unlike synaptic inhibition, is driven by extrasynaptic GABA receptors activated by the spill‐over of GABA outside of the synaptic cleft.…”

“…Using a lower concentration (100 U/mL) than the studies listed above, a 3 h exposure of IFNγ increased the frequency of spontaneous postsynaptic currents (sIPSCs) and tonic inhibition in rat hippocampal CA1 pyramidal neurons. 74 Tonic inhibition, unlike synaptic inhibition, is driven by extrasynaptic GABA receptors activated by the spill-over of GABA outside of the synaptic cleft. It is regulated by balancing GABA release and re-uptake as well as GABA receptor composition and trafficking.…”