Traumatic brain injury (TBI) can be caused by a penetrating force, hit to the head, or rotating injury from high impact sports, falls, and/or automobile accidents (C. Xu et al., 2022), (Cheng et al., 2019), (Namjoshi et al., 2014). TBI-related injuries manifest as a myriad of physiological, behavioral, and neuropsychiatric symptoms that can persist months to years (Das et al., 2022; Howe et al., 2022). Mild TBI, contributes to the largest proportion of TBI injuries and can have detrimental neurodegenerative outcomes as repetitive injuries accumulate over time (Moro et al., 2022). In addition, TBI is a heterogeneous disorder that has a multitude of pathologies (Das et al., 2022), such as: cerebral blood flow (CBF) derangements (Das et al., 2022), (Stephens et al., 2018), (Li et al., 2020), blood-brain barrier (BBB) permeability/leakage (George et al., 2022), (Szarka et al., 2019), (Huang et al., 2023), and mitochondrial dysfunction (Sun et al., 2022) (Demers-Marcil and Coles, 2022), (Du et al., 2022), (S. Zhang et al., 2022), which all serve as areas of possible intervention.

In fact, decreased CBF post-TBI can increase the severity of injury as well as functional deficits (Ware et al., 2020), (Vedung et al., 2022). Disruption of the BBB can occur early after injury; and in some cases, persist years after injury often associated with poor outcomes (Cash and Theus, 2020). BBB leakage can occur even after a single mild TBI hit in humans, as detected via magnetic resonance imaging (George et al., 2022), (Johnson et al., 2013), (Wang and Li, 2016). Furthermore, leukocytes, as well as platelet aggregation (due to possible hemorrhage), have been observed to bind to the endothelium (via adhesion molecules) and migrate to the parenchyma to further contribute to secondary damage post-TBI (Hartl et al., 1997), (Schwarzmaier et al., 2010), (Schwarzmaier et al., 2013). Moreover, the brain is thought to consume ∼20% of the body's oxygen consumption for oxidative phosphorylation and subsequent ATP production, therefore, even the slightest disturbance in mitochondrial bioenergetics and/or dynamics can have profound detrimental outcomes on neuronal function (Vagnozzi et al., 2007), (Kim et al., 2017). Repetitive and mild TBI (rmTBI) can cause mitochondrial dysfunction (Vagnozzi et al., 2007), (Balasubramanian et al., 2021) by altering oxygen consumption rates, as well as mitochondrial fission and fusion dynamics, that can affect overall functional outcomes in rmTBI patients (Khacho et al., 2017), (Moore et al., 2020).

Protein arginine methyltransferase 7 (PRMT7) is an emerging therapeutic target in various pre-clinical and clinical disease pathologies, such as in cancer (Oksa et al., 2022), (C. Liu et al., 2022), metastasis (L. Liu et al., 2021), delayed developmental disorders in humans (Poquerusse et al., 2022), (Agolini et al., 2018), and impaired social skills in murine knockout models (S. Y. Lee et al., 2020), (W. Zhang et al., 2021), (S. Y. Lee et al., 2019), (Ma et al., 2022), (Fiorica and Wheeler, 2019). PRMT7 has been shown to methylate the sodium leak channel, whereas PRMT7 knockout mice led to intrinsically higher neuronal excitability in the hippocampal dentate granule cells v. wild-type, to suggest PRMT7-mediated methylation is necessary to maintain neuronal resting membrane potential (S. Y. Lee et al., 2019). Additionally, the absence or knockdown of PRMT7 caused a decrease in hyperpolarization-activated cyclic nucleotide-gated channels protein levels and increased resting membrane potential of the CA1 region of the hippocampus (S. Y. Lee et al., 2020), further highlighting the importance of PRMT7 in learning/memory function. Furthermore, our recent investigations suggest a role for PRMT7 in our previous rmTBI studies that correlated with pathologies such as neuroinflammation (Acosta et al., 2023). This correlation between PRMT7 deficiency and pathology set the foundation for this study to investigate a functional role of PRMT7 by using AAV gene therapy. Here, we report that the in vivo overexpression of PRMT7 prevented neurovascular uncoupling, BBB permeability/leakage, increased leukocyte rolling, and improved mitochondrial function, to further delineate a functional role for PRMT7 in rmTBI.