The causes of autism spectrum disorders and of epilepsy are poorly understood. A major genetic link to these neurodevelopmental disorders is the mTOR pathway. mTOR is a protein kinase that regulates translation and autophagy. This proposal seeks to test the hypothesis that a transporter of amino acids regulates the mTOR pathway in newborn neurons during cerebral cortical development. Patients that harbor copy number variations or with mutations that ultimately effect the expression of this gene present with a spectrum of neuropathological manifestations including epilepsy, autism, and intellectual delay. While the precise association of the amino acid transporter with the manifestations is still unknown, here we propose that changes in expression alter mTOR activity and neuron morphology.
In aim 1 we propose to determine whether and at what times in development the transporter regulates mTOR pathway. Additional experiments include examining the downstream pathways and cellular consequences of manipulating the transporter.
In aim 2 we propose to examine the cellular consequences of altering expression of the amino acid transporter. More specifically, we plan to examine neuron morphology including dendrite arborization in vivo following over- expression or knockdown of the transporter.
In aim 3 we propose to determine whether morphological changes caused by manipulations of the transporter are due to aberrant mTOR pathway activity. We first will perform experiments using reversible shRNAs and shRNA resistant constructs to define the extent and timing for which morphology can be rescued. Finally, we will define whether changes in neuron morphology caused by aberrant expression of the transporter can be reversed or prevented by manipulating the mTOR pathway.
Mutations in genes that alter the activity of a protein kinase called mTOR can result in a spectrum of neurological disorders that have manifestations ranging from autism to epilepsy. Experiments will be performed to define a role for an amino acid transporter in the developing brain for one of the upstream regulators of the mTOR pathway. If successful these experiments may lead to new treatment options for patients with mutations in the mTOR pathway.
| Sokolov, Aidan M; Seluzicki, Caitlin M; Morton, Mary C et al. (2018) Dendrite growth and the effect of ectopic Rheb expression on cortical neurons. Neurosci Lett 671:140-147 |
