ABSTRACT
The majority of axons in the central nervous system (CNS) are wrapped with compact layers of myelin sheaths
to ensure the rapid transmission of neuronal signals over long distances. As myelin thickness and sheath
length have profound effects on conduction velocity, myelination is also crucial to the precise control of
spatiotemporal activity patterns in the CNS. In the mammalian spinal cord, both descending motor and
ascending sensory pathways travel over long distances, requiring fine control of conduction speed necessary
for sensory-motor integration. Myelin disruption in the spinal cord after CNS trauma or disease, like multiple
sclerosis, causes axonal conduction failure leading to severe impairment of neurological function.
Accumulating data support the notion that neuronal activity positively regulates myelin development and also
induces adaptive myelin plasticity in adulthood. However, the underlying mechanisms are still not fully
understood, and no molecular mediators have been identified regulating this process. Alpha2delta1 (A2d1)
subunits of voltage-gated Ca2+ channels (VGCCs) positively regulate the plasma membrane expression and
the biophysical properties of VGCCs, including those controlling synaptic vesicle release. Our preliminary data
suggest that A2d1 subunits positively regulate myelin development in the murine spinal cord. Building on our
promising data, the proposed study aims at dissecting the neuronal- and glial-specific mechanisms underlying
the role of A2d1 subunits in myelin development and repair. We propose a series of gain- and loss-of-function
experiments to investigate how A2d1 subunits expressed in neurons and oligodendrocyte precursor cells
positively regulate myelin development. Additionally, we will test whether manipulating A2d1 subunits
effectively promotes remyelination and functional recovery after demyelinating injury. Overall, this study will
shed light on the molecular mechanisms underlying activity-dependent myelin formation and plasticity and
contribute to the design of translational research aimed at restoring myelin and neurological function after CNS
trauma and disease.