Synaptic disruption is a prelude to and often a primary cause of neurological disease but we have fewstrategies to correct dysmorphic synapses even if they occur early in the degenerative process. Growthcontrol pathways i.e. those that promote protein and lipid synthesis while reducing catabolism regulatesynaptic form that in turn ensures efficient function and plasticity. The 7-pass endosomal membrane proteinTMEM184B regulates synaptic structure and function across species; accordingly its loss causes exuberantsynaptic sprouting swollen nerve terminals and altered excitability. In humans disruption of conserved aminoacids in TMEM184B is linked to nervous system disruptions including microcephaly intellectual disabilitycorpus callosum hypoplasia and epilepsy. While TMEM184B genetic disruptions are rare the disordersproduced by TMEM184B disruption are common suggesting an intersection with key neurological pathways. Our long-term goal is to define the mechanisms underlying TMEM184B variant-associated nervous systemdisorders in order to provide mechanistic guidance for their treatment. Our overall objectives in this proposalare to determine how TMEM184B directs key signaling pathways supporting neuronal structure and functionand to illuminate how patient variants of TMEM184B alter synaptic transmission and resultant behavior.TMEM184B has sequence similarity to bile acid and sterol transporters but this proposed molecular functionremains untested. Preliminary data and published studies suggest an intersection between TMEM184B andmTOR but how TMEM184B influences mTOR pathway activity is completely unknown. We hypothesize that TMEM184B is an endosomal transporter whose function impacts mTORC1 signalingto promote synaptic structure and function. In Aim1 we will evaluate the specific contributions of TMEM184Bto the mTORC1 pathway using primary cortical neuron cultures from wild type and TMEM184B mutant mice.We will evaluate the function of upstream activators and downstream effectors of mTORC1 using functionalreadouts as well as lipidomic and phospho-proteomic tools. In Aim 2 we will model human disease-linkedTMEM184B variants in Drosophila by introducing patient mutations into conserved amino acids. With theseflies we will evaluate synaptic form function (electrophysiological recording) and behavior. In Aim 3 we willestablish the molecular function of the TMEM184B protein using a combination of in silico thermodynamicand proteomic assays to reveal candidate transport substrates and other metabolites most affected byTMEM184B disruption. Overall our multifaced approach will illuminate the mechanism through whichTMEM184B acts to ensure synaptic morphology and function while enabling a better classification ofTMEM184B-associated disorders with others of similar etiology facilitating improved diagnosis and treatment.