Abstracts

Rationale: Following a traumatic brain injury (TBI), post-traumatic epilepsy (PTE) can occur. The latent period between a TBI and the onset of PTE provides a therapeutic opportunity to prevent the pathophysiological changes that result in a seizure-prone network. Post-traumatic epileptogenesis may be explained by a loss of network inhibition resulting in an excitatory/inhibitory imbalance of the network. By targeting the metabolic changes following TBI, namely acute increases in glycolysis, we may be able to prevent the downstream loss of interneurons and resulting hyperexcitability. We hypothesize that 2-deoxyglucose (2DG), a glucose analog that competitively inhibits glycolysis at the rate-limiting enzyme hexokinase, is neuroprotective and anti-epileptogenic following TBI. Methods: To study TBI, we used controlled cortical impact (CCI) in mice.  We study both acute 2DG treatment in slices and chronic (7 day) 2DG treatment in vivo. We use electrophysiological and immunohistochemical approaches to examine the excitability of the perilesional network, the presence of interneurons in the perilesional area, and the intrinsic excitability of different neuronal subtypes in the presence of 2DG. Results: In vitro 2DG application attenuated epileptiform activity in acute cortical slices from injured brains (% Epileptiform sweeps: CCI baseline = 90% versus CCI 2DG wash-on = 18%; n = 10 slices; Paired sample t-test, p = 2.2E-6). Additionally, in vivo 2DG treatment prevented the development of epileptiform activity following injury (% Epileptiform sweeps: CCI vehicle = 95% versus CCI 2DG = 13.3%; n = 10 slices, 9 slices; 2-sample t-test, p = 1.8E-9). In vivo 2DG treatment also attenuated the loss of parvalbumin-expressing interneurons in the region adjacent to the lesion site (PV+ cell density/10,000um^2: Sham vehicle = 12.51, Sham 2DG = 11.66, CCI vehicle = 6.28, CCI 2DG = 12.02; n = 5 animals/group; ANOVA Sham vehicle vs. CCI vehicle, p = 0.013; CCI vehicle vs. CCI 2DG, p = 0.018). Preliminary data suggests that in vivo 2DG rescues the increase in sEPSC and the decrease in sIPSC frequency observed after CCI. Finally, we have observed that 2DG has cell type-specific effects on excitability – 2DG treatment in naïve acute cortical slices results in a decrease in the excitability and membrane resistance of excitatory pyramidal neurons, but not inhibitory interneurons (Current required to elicit first action potential in 2DG versus at baseline: Excitatory = 66.07 pA, Inhibitory = -6.25 pA; n = 8 cells; 2-sample t-test, p = 0.041; Change in membrane resistance with 2DG: Excitatory = -40.4%, Inhibitory = -5.4%; n = 8 cells; 2-sample t-test, p = 0.017). Conclusions: Our research supports a role for glycolytic inhibition in the preservation of interneurons and the prevention of epileptogenesis following TBI. Additionally, it may reveal a novel cell type-specific coupling of metabolism to neuronal excitability. Funding: NINDS -- F31 NS101741 (JBK), R21 NS098009, R01 NS076885 (CD)