Synaptic Pathology in Traumatic Brain Injury and Therapeutic Insights

Traumatic brain injury (TBI) results in a cascade of neuropathological events, which can significantly disrupt synaptic integrity. This review explores the acute, subacute and chronic phases of synaptic dysfunction and loss in trauma which commence post-TBI, and their contribution to the subsequent neurological sequelae. Central to these disruptions is the loss of dendritic spines and impaired synaptic plasticity, which compromise neuronal connectivity and signal transmission. During the acute phase of TBI, mechanical injury triggers presynaptic glutamate secretion and Ca²⁺ ion-mediated excitotoxic injury, accompanied by cerebral edema, mitochondrial dysfunction and the loss of the mushroom-shaped architecture of the dendritic spines. The subacute phase is marked by continued glutamate excitotoxicity and GABAergic disruption, along with neuroinflammatory pathology and autophagy. In the chronic phase, long-term structural remodeling and reduced synaptic densities are evident. These chronic alterations underlie persistent cognitive and memory deficits, mood disturbances and the development of post-traumatic epilepsy. Understanding the phase-specific progression of TBI-related synaptic dysfunction is essential for targeted interventions. Novel therapeutic strategies primarily focus on how to effectively counter acute excitotoxicity and neuroinflammatory cascades. Future approaches may benefit from boosting synaptic repair and modulating neurotransmitter systems in a phase-specific manner, thereby mitigating the long-term impact of TBI on neuronal function.