The causes of autism spectrum disorders and of epilepsy are poorly understood. A major genetic link to theseneurodevelopmental disorders is the mTOR pathway. mTOR is a protein kinase that regulates translation andautophagy. This proposal seeks to test the hypothesis that a transporter of amino acids regulates the mTORpathway in newborn neurons during cerebral cortical development. Patients that harbor copy number variationsor with mutations that ultimately effect the expression of this gene present with a spectrum ofneuropathological manifestations including epilepsy, autism, and intellectual delay. While the preciseassociation of the amino acid transporter with the manifestations is still unknown, here we propose thatchanges in expression alter mTOR activity and neuron morphology. In aim 1 we propose to determine whetherand at what times in development the transporter regulates mTOR pathway. Additional experiments includeexamining the downstream pathways and cellular consequences of manipulating the transporter. In aim 2 wepropose to examine the cellular consequences of altering expression of the amino acid transporter. Morespecifically, 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 changescaused by manipulations of the transporter are due to aberrant mTOR pathway activity. We first will performexperiments using reversible shRNAs and shRNA resistant constructs to define the extent and timing for whichmorphology can be rescued. Finally, we will define whether changes in neuron morphology caused by aberrantexpression of the transporter can be reversed or prevented by manipulating the mTOR pathway.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
