CRF Mediates Stress-Induced Pathophysiological High-Frequency Oscillations in Traumatic Brain Injury

It is not known why there is increased risk to have seizures with increased anxiety and stress after traumatic brain injury (TBI). Stressors cause the release of corticotropin-releasing factor (CRF) both from the hypothalamic pituitary adrenal (HPA) axis and from CNS neurons located in the central amygdala and GABAergic interneurons. We have previously shown that CRF signaling is plastic, becoming excitatory instead of inhibitory after the kindling model of epilepsy. Here, using Sprague Dawley rats we have found that CRF signaling increased excitability after TBI. Following TBI, CRF type 1 receptor (CRFR(1))-mediated activity caused abnormally large electrical responses in the amygdala, including fast ripples, which are considered to be epileptogenic. After TBI, we also found the ripple (120–250 Hz) and fast ripple activity (>250 Hz) was cross-frequency coupled with θ (3–8 Hz) oscillations. CRFR(1) antagonists reduced the incidence of phase coupling between ripples and fast ripples. Our observations indicate that pathophysiological signaling of the CRFR(1) increases the incidence of epileptiform activity after TBI. The use for CRFR(1) antagonist may be useful to reduce the severity and frequency of TBI associated epileptic seizures.