Reduced inhibition of hippocampal adult-born granule cells by parvalbumin interneurons after TBI.

Traumatic brain injury (TBI) is one of the leading causes of acquired temporal lobe epilepsy. TBI drives hippocampal circuit rearrangements that may contribute to increased seizure risk, such as altered inhibitory circuit function and aberrant post-traumatic neurogenesis. In the hippocampal dentate gyrus, adult-born dentate granule cells (DGCs) acquire inhibitory synaptic inputs from parvalbumin-expressing (PV) interneurons early in their maturation. PV inputs are important for circuit integration and feedforward inhibition of adult-born DGCs. We used genetically modified mice, retroviral vectors, and optogenetics to study adult-born and mature DGCs after a Controlled Cortical Impact model of TBI. We tested whether TBI altered PV-mediated inhibition of DGCs that were born after TBI. DGCs born after TBI acquired inhibitory synaptic inputs during their maturation, but PV-mediated inhibition of adult-born DGCs was persistently reduced following TBI. In contrast, mature granule cells did not have a reduction in PV-mediated inhibitory synaptic inputs following TBI. The density of PV cells in the dentate gyrus was not different after TBI, therefore functional changes were not due to loss of PV neurons. The deficit in PV-mediated functional innervation of adult-born DGCs was associated with a transient reduction in release probability at these synapses, which normalized as DGCs matured despite ongoing reduction of functional PV input. Surprisingly, although spontaneous inhibitory postsynaptic currents were reduced for mature granule cells after TBI, there was no difference in spontaneous inhibitory postsynaptic currents in adult-born DGCs. Taken together, these data demonstrate distinct differences in the de novo development and maintenance of PV synapses in the dentate gyrus after TBI. The addition of neurons with reduced PV interneuron-mediated feed-forward inhibition to the dentate gyrus could contribute to hippocampal hyperexcitability after severe brain injury.