Assessment of Neurobehavioral Performance and Markers of Synaptic Vesicle Trafficking in an Alpha-Synuclein Knockout Mouse Model after Controlled Cortical Impact Injury

Traumatic brain injury (TBI) is associated with significant deficits across cognitive, emotional, and somatic functions, contributing to reduced quality of life for TBI survivors. Synaptic vesicle cycling, crucial for neurotransmitter release, involves a tightly regulated process of exocytosis and endocytosis, of which monomeric alpha-synuclein (mAS) is implicated in both, and therefore, may underpin neurotransmission impairments post-TBI. Our team previously demonstrated that controlled cortical impact (CCI) reduces hippocampal and cortical mAS in the weeks postinjury. We hypothesized that genetic knockout (KO) of mAS expression may exacerbate TBI-induced deficits in neurobehavioral performance and synaptic health. To elucidate the role of AS in neurobehavioral recovery and histopathological alterations post-TBI, we employed a genetic AS-KO mouse model (B6;129X1-Snca<tm1Ros1>/J). Markers of exocytosis and endocytosis, cysteine-string protein alpha (CSPα) and clathrin light chain (CLC), respectively, and the astrocytic marker glial fibrillary acidic protein (GFAP) were assessed. Male AS-KO and wild-type (WT) littermate controls received 1.8 mm CCI or Sham control surgery (Sham-WT, CCI-WT, CCI-KO, <i>n</i> = 10/group). Beam balance testing (1-5 days) did not reveal differences in balance latency between groups. Spatial learning (Morris water maze, 9-13 days) was significantly impaired in both CCI groups relative to Sham-WT controls, whereas the CCI-KO mice performed comparably to Sham-WT mice in spatial memory testing. Following CCI, GFAP expression was significantly elevated in the ipsilateral hemisphere, independent of genotype, compared to Sham controls. CCI also resulted in a reduction of CLC expression in the ipsilateral hemisphere, while CSPα expression remained unchanged in both hemispheres across all groups.