Synaptic Pathology in Traumatic Brain Injury and Therapeutic Insights

Abstract

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.

Keywords: excitotoxicity; glutamate; neuroinflammation; synaptic density; synaptic plasticity; traumatic brain injury.

Figure 1

Acute TBI and Excitotoxicity. Main excitotoxic events in acute TBI include increased activity of the SNARE proteins supporting increased glutamatergic exocytosis and binding at the postsynaptic NMDAr and AMPAr, along with increases in the postsynaptic Ca²⁺ and Na⁺ ion influx. Excess glutamate is recycled by neighboring astrocytes. Downstream activation of Ca²⁺-mediated enzyme pathways leads to cytoskeletal breakdown and further boosts the production of reactive oxygen species, thereby potentiating mitochondrial damage. Moreover, Ca²⁺-mediated calpain activation leads to the activation of cytochrome c (cytC), truncated apoptosis-inducing factor (tAIF) and endonuclease G (endoG), which are implicated in DNA lysis. Calpain also blocks the Na⁺-Ca²⁺ exchanger, thereby limiting outflow of Ca²⁺ ions and further potentiating intracellular calcium toxicity [67].

Figure 2

Neuroinflammation as a result of TBI. Proinflammatory cytokines leak through the blood–brain barrier and initiate activation of microglia and dendritic cells, thereby potentiating astrocytic proliferation and astrogliosis. This further boosts the secretion of proinflammatory cytokines (tumor necrosis factor: TNF-α, interleukins-1α, interleukin-6 and gamma-interferon) (IFN-γ). Further highlights of the subacute phase in TBI include increased glutamatergic activity, loss of inhibitory interneurons and breakdown of GABA signaling. Moreover, production of anti-inflammatory cytokines also occurs to resolve neuroinflammation [74,75].