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Reductions in Synaptic Vesicle Glycoprotein 2 Isoforms in the Cortex and Hippocampus in a Rat Model of Traumatic Brain Injury

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Abstract

Traumatic brain injury (TBI) can produce lasting cognitive, emotional, and somatic difficulties that can impact quality of life for patients living with an injury. Impaired hippocampal function and synaptic alterations have been implicated in contributing to cognitive difficulties in experimental TBI models. In the synapse, neuronal communication is facilitated by the regulated release of neurotransmitters from docking presynaptic vesicles. The synaptic vesicle glycoprotein 2 (SV2) isoforms SV2A and SV2B play central roles in the maintenance of the readily releasable pool of vesicles and the coupling of calcium to the N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex responsible for vesicle docking. Recently, we reported the findings of TBI-induced reductions in presynaptic vesicle density and SNARE complex formation; however, the effect of TBI on SV2 is unknown. To investigate this, rats were subjected to controlled cortical impact (CCI) or sham control surgery. Abundance of SV2A and SV2B were assessed at 1, 3, 7, and 14 days post-injury by immunoblot. SV2A and SV2B were reduced in the cortex at several time points and in the hippocampus at every time point assessed. Immunohistochemical staining and quantitative intensity measurements completed at 14 days post-injury revealed reduced SV2A immunoreactivity in all hippocampal subregions and reduced SV2B immunoreactivity in the molecular layer after CCI. Reductions in SV2A abundance and immunoreactivity occurred concomitantly with motor dysfunction and spatial learning and memory impairments in the 2 weeks post-injury. These findings provide novel evidence for the effect of TBI on SV2 with implications for impaired neurotransmission neurobehavioral dysfunction after TBI.

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Data Availability

All data generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This work was supported by the National Institutes of Health Grant 1R21NS111099 (SWC) and 5R01NS079061 (CED), The Chuck Noll Foundation (SWC), and the Walter L. Copeland Fund of The Pittsburgh Foundation (SWC).

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  1. Neurological Surgery, University of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA, 15224, USA

    Katherine M. Fronczak, Youming Li, Jeremy Henchir, C. Edward Dixon & Shaun W. Carlson

  2. VA Pittsburgh Healthcare System, Pittsburgh, PA, USA

    C. Edward Dixon

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  1. Katherine M. Fronczak
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KMF, YL, JH, CED, and SWC completed the investigation; KMF and SWC completed data curation and analysis; KMF, CED, and SWC drafted, edited, and revised the manuscript.

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Correspondence to Shaun W. Carlson.

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Research involving human participants: Not applicable. Research involving welfare of animal subjects: All experimental procedures were approved by the University of Pittsburgh Institutional Animal Care and Use Committee in accordance with the guidelines established by the National Institutes of Health in the Guide for the Care and Use of Laboratory Animals.

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Fronczak, K.M., Li, Y., Henchir, J. et al. Reductions in Synaptic Vesicle Glycoprotein 2 Isoforms in the Cortex and Hippocampus in a Rat Model of Traumatic Brain Injury. Mol Neurobiol 58, 6006–6019 (2021). https://doi.org/10.1007/s12035-021-02534-3

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