Selective enhancement of GABAergic inhibition is thought to impact many vital brain functions and interferes with the genesis and/or progression of numerous brain disorders. Here, we show that selectively increasing nMDA receptor activity in inhibitory neurons using an nMDAR positive allosteric modulator (pAM) elevates spiking activity of inhibitory neurons in vitro and in vivo. in vivo infusion of pAM increases spontaneous and sound-evoked spiking in inhibitory and decreases spiking in excitatory neurons, and increases signal-to-noise ratio in the primary auditory cortex. in addition, pAM infusion prior to noise trauma prevents the occurrence of tinnitus and reduction in GABAergic inhibition. these results reveal that selectively enhancing endogenous nMDAR activity on the GABAergic neurons can effectively enhance inhibitory activity and alter excitatory-inhibitory balance, and may be useful for preventing diseases that involve reduced inhibition as the major cause.

Neuroinflammation has been implicated in noise-induced auditory processing disorder and tinnitus. Certain non-auditory neurological disorders can also increase the levels of proinflammatory cytokines in the brain. To investigate the impact of increased brain proinflammatory cytokine levels on the central auditory pathway, we infused recombinant TNF-α into the right lateral cerebral ventricle, and examined auditory processing and cytoarchitecture of the auditory cortex. Microglial deramification was observed in the auditory cortex of mice that had received both TNF-α infusion and exposure to an 86-dB noise, but not in mice that had received either TNF-α infusion or noise exposure alone. In addition, we observed reduced cortical PV+ neuron density and impaired performances in gap detection and prepulse inhibition (PPI) only in mice that received both TNF-α infusion and the noise exposure. These results suggest that disease-related increase in brain proinflammatory cytokine release could be a risk factor for noise-induced auditory processing disorder and tinnitus.

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BackgroundN-methyl-D-aspartate receptor (NMDAR) hypofunction has been proposed to underlie the pathogenesis of schizophrenia. Specifically, reduced function of NMDARs leads to altered balance between excitation and inhibition which further drives neural network malfunctions. Clinical studies suggested that NMDAR modulators (glycine, D-serine, D-cycloserine and glycine transporter inhibitors) may be beneficial in treating schizophrenia patients. Preclinical evidence also suggested that these NMDAR modulators may enhance synaptic NMDAR function and synaptic plasticity in brain slices. However, an important issue that has not been addressed is whether these NMDAR modulators modulate neural activity/spiking in vivo.MethodsBy using in vivo calcium imaging and single unit recording, we tested the effect of D-cycloserine, sarcosine (glycine transporter 1 inhibitor) and glycine, on schizophrenia-like model mice.ResultsIn vivo neural activity is significantly higher in the schizophrenia-like model mice, compared to control mice. D-cycloserine and sarcosine showed no significant effect on neural activity in the schizophrenia-like model mice. Glycine induced a large reduction in movement in home cage and reduced in vivo brain activity in control mice which prevented further analysis of its effect in schizophrenia-like model mice.ConclusionsWe conclude that there is no significant impact of the tested NMDAR modulators on neural spiking in the schizophrenia-like model mice.

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