Insights into the Cellular Basis of Posttraumatic Epilepsy
Authors: Benardo Larry S. 
Published: December 2022

Physiological and Structural Evidence for Hippocampal Involvement in Persistent Seizure Susceptibility after Traumatic Brain Injury

Golarai G, Greenwood AC, Feeney DM, Connor JA

J Neurosci 2001;21:8523–8537

Epilepsy is a common outcome of traumatic brain injury (TBI), but the mechanisms of posttraumatic epileptogenesis are poorly understood. One clue is the occurrence of selective hippocampal cell death after fluid-percussion TBI in rats, consistent with the reported reduction of hippocampal volume bilaterally in humans after TBI and resembling hippocampal sclerosis, a hallmark of temporal-lobe epilepsy. Other features of temporal-lobe epilepsy, such as long-term seizure susceptibility, persistent hyperexcitability in the dentate gyrus (DG), and mossy fiber synaptic reorganization, however, have not been examined after TBI. To determine whether TBI induces these changes, we used a well studied model of TBI by weight drop on somatosensory cortex in adult rats. First, we confirmed an early and selective cell loss in the hilus of the DG and area CA3 of hippocampus, ipsilateral to the impact. Second, we found persistently enhanced susceptibility to pentylenetetrazole-induced convulsions 15 weeks after TBI. Third, by applying GABAA antagonists during field-potential and optical recordings in hippocampal slices 3 and 15 weeks after TBI, we unmasked a persistent, abnormal APV-sensitive hyperexcitability that was bilateral and localized to the granule cell and molecular layers of the DG. Finally, using Timm histo-chemistry, we detected progressive sprouting of mossy fibers into the inner molecular layers of the DG bilaterally 2–27 weeks after TBI. These findings are consistent with the development of posttraumatic epilepsy in an animal model of impact head injury, showing a striking similarity to the enduring behavioral, functional, and structural alterations associated with temporal-lobe epilepsy.

Long-Term Hyperexcitability in the Hippocampus After Experimental Head Trauma

Santhakumar V, Ratzliff AD, Jeng J, Toth Z, Soltesz I

Ann Neurol 2001;50:708–717

Head injury is a causative factor in the development of temporal lobe epilepsy. However, whether a single episode of concussive head trauma causes a persistent increase in neuronal excitability in the limbic system has not been unequivocally determined. This study used the rodent fluid percussion injury (FPI) model, in combination with electrophysiological and histochemical techniques, to investigate the early (1 week) and long-term (1 month or longer) changes in the hippocampus after head trauma. Low-frequency, single-shock stimulation of the perforant path revealed an early granule cell hyperexcitability in head-injured animals that returned to control levels by 1 month. However, there was a persistent decrease in threshold to induction of seizure-like electrical activity in response to high-frequency tetanic stimulation in the hippocampus after head injury. Timm staining revealed both early- and long-term mossy fiber sprouting at low to moderate levels in the dentate gyrus of animals that experienced FPI. There was a long-lasting increase in the frequency of spontaneous inhibitory postsynaptic currents in dentate granule cells after FPI, and ionotropic glutamate receptor antagonists selectively decreased the spontaneous inhibitory postsynaptic current frequency in the head-injured animals. These results demonstrate that a single episode of experimental closed head trauma induces long-lasting alterations in the hippocampus. These persistent structural and functional alterations in inhibitory and excitatory circuits are likely to influence the development of hyperexcitable foci in posttraumatic limbic circuits.