Abstracts

Rationale: As the prevalence of traumatic brain injury (TBI) continues to grow, there is increasing awareness of its diverse and devastating neuro-psychiatric consequences. Developing novel therapies to mitigate TBI-related conditions is challenging, as their pathophysiology is not well understood and likely involves diverse molecular and cellular changes following brain injury.   Here, we focus on the role of GABAergic interneuron (IN) dysfunction as a key cellular event in post-TBI pathophysiology and the development post-traumatic hyperexcitability and epilepsy.  Specifically, we focus on parvalbumin-expressing (PV+) INs, which are critical to cortical function and to maintaining inhibitory control of cortical circuits. PV immunoreactivity is lost following TBI in both humans and in animal models, and the cortical network hyperexcitability observed after injury may be a direct result of this inhibitory network dysfunction.  Preserving inhibitory circuit function after TBI offers significant promise in maintaining physiologic brain function and reducing network hyperexcitability.  With that goal in mind, we utilized a common, clinically available glycolytic inhibitor, 2-deoxyglucose (2-DG), to attempt to preserve inhibitory network function following TBI.  The rationale behind this approach is based on the ketogenic diet, a powerful dietary anticonvulsant and neuroprotective therapy where ketosis (and ketone bodies) replaces glycolysis (and glucose) as a principle energy supply of the brain. Methods: Traumatic brain injury was modeled with controlled cortical impact (CCI), a commonly used rodent model of TBI, as previously published.  Animals were then injected with 250 mg/kg 2-deoxyglucose (2DG) dissolved in sterile saline or vehicle. The first dose was administered immediately after CCI or sham surgery, and the doses were continued daily for 7 days. Animals were then sacrificed 14-28 days after CCI and prepared for brain slice electrophysiology (whole cell recording and field recording) or immunohistochemistry. Results: Here, we show that glycolytic inhibition with 2-DG reduces the intrinsic excitability of excitatory pyramidal neurons, but not inhibitory INs, suggesting that these different neuronal subtypes couple glycolysis to excitability in different ways. In line with this, we report that acute treatment with 2-DG reversibly attenuates abnormal, epileptiform activity seen in brain slices 3-5 weeks following controlled cortical impact (CCI).  To determine if 2-DG also has beneficial effects in vivo, we treated animals systemically with 2-DG for one week following CCI and assayed known pathophysiological consequences of TBI, including network hyperexcitability, loss of PV+ INs, and synaptic dysfunction 3-5 weeks following injury.  In vivo 2-DG treatment attenuated all of these CCI-related pathologies.  Using genetic labeling strategies, we found that in addition to a loss of PV INs, there is an additional loss of PV expression in the surviving cells. We showed that in vivo 2-DG rescues the injury-induced changes in PV expression, which could explain its protective effects on cortical hyperexcitability and synaptic activity. Conclusions: Inhibiting glycolysis using 2-DG appears to maintain PV expression and effectively preserve inhibitory network function following TBI. In total, our study supports a cell type-specific coupling of metabolism to neuronal excitability, and strongly supports the further development of 2-DG as a treatment following TBI. Funding: DOD EP160021