Adult Born Dentate Granule Cell Mediated Upregulation of Feedback Inhibition in a Mouse Model of Traumatic Brain Injury

Abstract

Post-traumatic epilepsy (PTE) and behavioral comorbidities frequently develop after traumatic brain injury (TBI). Aberrant neurogenesis of dentate granule cells (DGCs) after TBI may contribute to the synaptic reorganization that occurs in PTE, but how neurogenesis at different times relative to the injury contributes to feedback inhibition and recurrent excitation in the dentate gyrus is unknown. Thus, we examined whether DGCs born at different postnatal ages differentially participate in feedback inhibition and recurrent excitation in the dentate gyrus using the controlled cortical impact (CCI) model of TBI. Both sexes of transgenic mice expressing chan-nelrhodopsin2 (ChR2) in postnatally born DGCs were used for optogenetic activation of three DGC cohorts: postnatally early born DGCs, or those born just before or after CCI. We performed whole-cell patch-clamp recordings from ChR2-negative, mature DGCs and parvalbumin-expressing basket cells (PVBCs) in hippocampal slices to determine whether optogenetic activation of postnatally born DGCs increases feedback inhibition and/or recurrent excitation in mice 8-10 weeks after CCI and whether PVBCs are targets of ChR2-positive DGCs. In the dentate gyrus ipsilateral to CCI, activation of ChR2-expressing DGCs born before CCI produced increased feedback inhibition in ChR2-negative DGCs and increased excitation in PVBCs compared with those from sham controls. This upregulated feedback inhibition was less prominent in DGCs born early in life or after CCI. Surprisingly, ChR2-positive DGC activation rarely evoked recurrent excitation in mature DGCs from any cohort. These results support that DGC birth date-related increased feedback inhibition in of DGCs may contribute to altered excitability after TBI.

Early Deficits in Dentate Circuit and Behavioral Pattern Separation after Concussive Brain Injury

“…However previous studies have identified post-FPI loss of PV neurons restricted to the dentate hilus and altered inhibition after FPI (Santhakumar et al, 2000; Folweiler et al, 2020). Whereas loss of immature and highly excitable adult born neurons born prior to injury could contribute to deficits in encoding novel object location, studies using the cortical impact injury have reported no loss of GCs born prior to injury (Kang et al, 2022). Rather, these neurons support enhanced feedback inhibition 8-10 weeks after injury.…”

Activation of hypoactive parvalbumin-positive fast-spiking interneuron restores dentate inhibition to prevent epileptiform activity in the mouse intrahippocampal kainate model of temporal lobe epilepsy

“…Intrinsic and synaptic properties of dentate PV+ interneurons were measured as we previously described (Kang et al, 2022). Briefly, their intrinsic properties were measured from voltage responses to a series of 1 second hyperpolarizing and depolarizing current steps (-200 to +600 pA, +40 pA increments) from –60mV.…”

“…Increased synaptic excitation of dentate PV+ interneurons develops in a mouse model of traumatic brain injury along with reduced AP frequency rate (Kang et al, 2022). We thus examined whether synaptic excitation of PV+ interneurons was also upregulated in TLE mice 4-6 weeks after IHK injection.…”

“…Dentate PV+ interneurons not only undergo reduced synaptic excitation, but also participate in downregulated PV+ interneuron mediated inhibition of DGCs early after status epilepticus and in epileptic tissues (Proddutur et al, 2023; Zhang and Buckmaster, 2009). However, surviving dentate PV+ interneurons manifest reduced AP generation, but increased synaptic excitation mediated by DGCs weeks after epileptogenic insults (e.g., traumatic brain injury), thus contributing to increased feedback inhibition in injured mice (Kang et al, 2022). It is unclear whether there are similar dentate PV+ interneuron associated compensatory changes in the chronic phase of TLE not associated with a traumatic brain injury.…”

Adult-Generated Dentate Granule Cells in Epilepsy: Loyal Gatekeepers or Evil Changelings?

“…As post-traumatic epilepsy (PTE) is a common form of acquired epilepsy in people, Kang and colleagues have begun to address these gaps in knowledge through their examination of adult neurogenesis in the controlled cortical impact (CCI) model of PTE. 6 Specifically, utilizing Gli1-CreER T2 , ChR2/eYFP (channelrhodopsin/enhanced yellow fluorescent protein) bitransgenic mice providing for tamoxifen-dependent control of cre-recombinase activity in neural progenitor cells, they selectively expressed a ChR2/eYFP fusion protein in 3 age-specific cohorts of granule cells: (1) postnatally generated cells that were mature at the time of the insult, (2) immature cells labeled just before CCI, and (3) newborn cells labeled just after CCI. Animals were examined 8 to 10 weeks after CCI, a time point at which spontaneous seizures are common in the model.…”