L-type voltage-gated calcium (Ca ²⁺ ) channels (L-VGCC) dysfunction is implicated in several neurological and psychiatric diseases. While a popular therapeutic target, it is unknown whether molecular mechanisms leading to disrupted L-VGCC across neurodegenerative disorders are conserved. Importantly, L-VGCC integrate synaptic signals to facilitate a plethora of cellular mechanisms; however, mechanisms that regulate L-VGCC channel density and subcellular compartmentalization are understudied. Herein, we report that in disease models with overactive mammalian target of rapamycin complex 1 (mTORC1) signaling (or mTORopathies), deficits in dendritic L-VGCC activity are associated with increased expression of the RNA-binding protein (RBP) Parkinsonism-associated deglycase (DJ-1). DJ-1 binds the mRNA coding for the alpha and auxiliary Ca ²⁺ channel subunits Ca _V 1.2 and α2δ2, and represses their mRNA translation, only in the disease states, specifically preclinical models of tuberous sclerosis complex (TSC) and Alzheimer’s disease (AD). In agreement, DJ-1-mediated repression of Ca _V 1.2/α2δ2 protein synthesis in dendrites is exaggerated in mouse models of AD and TSC, resulting in deficits in dendritic L-VGCC calcium activity. Finding of DJ-1-regulated L-VGCC activity in dendrites in TSC and AD provides a unique signaling pathway that can be targeted in clinical mTORopathies.

Traumatic brain injury (TBI) presents a major biomedical challenge due to its complex biomechanics and the heterogeneous cellular responses it elicits, including neuronal death, glial activation, and blood–brain barrier disruption. Traditional in vitro models, including 2D neuronal cultures, brain slices and transwell systems, have provided valuable insights into molecular and cellular biology but remain limited by their lack of human-specific architecture, vascularization, and neurovascular interactions. The purpose of this review is to systematically examine advances in in vitro TBI modeling, with particular attention to studies leveraging human induced pluripotent stem cell (iPSC)-derived neural and vascular tissues, organoids, hydrogel scaffolds, microfluidic platforms, and mechanical injury. We highlight how the integration of neurovascular unit (NVU) components has improved the physiological and functional relevance of these models. Finally, we identify key limitations, including variability in organoid maturation, incomplete vascularization, and lack of methodological standardization, and outline future directions for improving translational fidelity. Therefore, this review contributes to a critical evaluation of emerging technologies and their potential to advance neurotrauma research and therapeutic discovery.