The neuroprotective effect of ethanol intoxication in TBI is associated with the suppression of ErbB signaling in PV-positive interneurons.

Ethanol intoxication (EI) is a frequent comorbidity of TBI, but the impact of EI on TBI pathogenic cascades and prognosis is unclear: although clinical evidence suggests that EI may have neuroprotective effects, experimental support is, to date, inconclusive. We aimed at elucidating the impact of EI on TBI-associated neurological deficits, signaling pathways and pathogenic cascades, in order to identify new modifiers of TBI pathophysiology. We have shown that ethanol administration (5g/Kg) before trauma enhances behavioral recovery in a weight-drop TBI model; neuronal survival in the injured somatosensory cortex was enhanced by EI. We have used phospho- Receptor Tyrosine Kinase (RTK) arrays to screen the impact of ethanol on the TBI-induced activation of RTK in somatosensory cortex, identifying ErbB2/ErbB3 among the RTK activated by TBI and suppressed by ethanol. Phosphorylation of ErbB2/3/4 RTK was found upregulated in vGlut2+ excitatory synapses in the injured cortex, including excitatory synapses located on parvalbumin (PV)-positive interneurons. The administration of selective ErbB inhibitors was able recapitulate, to a significant extent, the neuroprotective effects of ethanol both on sensorimotor performance and structural integrity. Furthermore, suppression of PV interneurons in somatosensory cortex undergoing TBI, by engineered receptors with orthogonal pharmacology, could mimic the beneficial effects of ErbB inhibitors. Thus, we have shown that EI interferes with TBI-induced pathogenic cascades at multiple levels, with one prominent pathway, involving ErbB-dependent modulation of PV interneurons.