TNF-α Deficiency Reduces Parvalbumin Neuron Density, Impairs Homeostatic Plasticity, Disrupts Synaptic Excitation-Inhibition Balance and Prevents Critical Period Closure in the Auditory Cortex

Tumor necrosis factor-alpha (TNF-α), a pleiotropic cytokine, modulates neuronal functions under both physiological and pathological conditions. In the auditory system, it is required for refinement of the cortical frequency map during early development. In adulthood, TNF-α upregulation following noise trauma contributes to synaptic imbalance and central auditory processing deficits. The effects of TNF-α deficiency on adult auditory cortical circuits and function have not been examined. Here, we report that compared to wild-type (WT) control mice (an equal number of males and females per group), adult TNF-α knockout (KO) mice had reduced PV neuron density and PV expression levels. Pyramidal neurons in the auditory cortex of TNF-α KO mice had larger miniature excitatory postsynaptic current (mEPSC) amplitude and lower miniature inhibitory postsynaptic current (mIPSC) frequency, suggesting a shift in synaptic E/I balance. Cortical multiunit had increased spontaneous and evoked activity and broadened tuning bandwidth consistent with the increased synaptic E/I ratio. Importantly, unlike WT mice, TNF-α KO mice exhibited persistent critical period-like plasticity into adulthood. Following exposure to a single-frequency tone, the representation of the tone was enlarged in adult TNF-α KO mice, but not in WT mice. Together with existing literature, our results suggest that TNF-α has a bell-shaped influence on adult auditory cortical circuits, with both elevated and deficient TNF-α expression leading to PV neuron dysfunction, increased synaptic E/I ratio, and enhanced cortical frequency map plasticity. Significance Statement Tumor necrosis factor-α (TNF-α) is a pleiotropic cytokine that contributes to the regulation of synaptic excitation–inhibition (E/I) balance. Sensory restriction is associated with increased TNF-α expression and an elevated synaptic E/I ratio. Here, we show that TNF-α-deficient mice have reduced parvalbumin-positive (PV) inhibitory interneuron density, an increased E/I ratio, impaired sensory restriction-induced homeostatic plasticity, and persistent critical period-like plasticity in adulthood. Together, these findings suggest a nonlinear, bell-shaped relationship between TNF-α signaling and cortical circuit function, in which both excessive and deficient TNF-α levels are associated with impaired PV interneuron function and increased E/I ratio.