Traumatic brain injury diminishes feedforward activation of parvalbumin-expressing interneurons in the dentate gyrus.

Traumatic brain injury (TBI) is associated with aberrant network hyperexcitability in the dentate gyrus. GABAAergic parvalbumin-expressing interneurons (PV-INs) in the dentate gyrus regulate network excitability with strong, perisomatic inhibition, though the post-traumatic effects on PV-IN function after TBI are not well understood. In this study, we investigated physiological alterations in PV-INs one week after mild lateral fluid percussion injury (LFPI) in mice. PV-IN cell loss was observed in the dentate hilus after LFPI, with surviving PV-INs showing no change in intrinsic membrane properties. Whole-cell voltage clamp recordings in PV-INs revealed alterations in both excitatory and inhibitory postsynaptic currents (EPSCs/IPSCs). Evoked EPSCs in PV-INs from perforant path electrical stimulation were diminished after injury but could be recovered with application of a GABAA-receptor antagonist. Furthermore, current-clamp recordings using minimal perforant path stimulation demonstrated a decrease in evoked PV-IN action potentials after LFPI, which could be restored by blocking GABAAergic inhibition. Together, these findings suggest that injury alters synaptic input onto PV-INs, resulting in a net inhibitory effect that reduces feedforward PV-IN activation in the dentate gyrus. Decreased PV-IN activation suggests a potential mechanism of dentate gyrus network hyperexcitability contributing to hippocampal dysfunction after TBI.Significance Statement Traumatic brain injury (TBI) damages the hippocampus and causes long-lasting memory deficits. After TBI, the dentate gyrus, a crucial regulator of cortical input to the hippocampus, undergoes a dysfunctional net increase in excitation, though the circuit mechanisms underlying this network excitatory-inhibitory (E/I) imbalance are unclear. In this study, we found that TBI alters synaptic inputs onto an inhibitory interneuron population (PV-INs) in the dentate gyrus which results in the decreased firing activity of these neurons due to a net inhibitory influence. The inhibition of PV-INs demonstrates a potential mechanism contributing to dentate gyrus network hyperexcitability and hippocampal dysfunction after TBI.