Scalable, all-optical assays of synaptic function and plasticity

Project Summary In spite of the prevalence and severity of many neurological disordersthe development of new classes of drugs has been sluggish for decadesThe lack of new therapeutics is duein partto challenges in replicating the relevant biology in robustscalable in vitro assaysSynaptic dysfunctionin particularhas been implicated in a number of devastating neurological disorders including epilepsyAlzheimer s diseaseParkinson s diseaseAutism Spectrum DisorderASDschizophreniadepressionADHD and Huntington s diseaseCurrent approaches to measuring synaptic function suffer from the difficulty of stimulating the pre synaptic cell and recording from the post synaptic cell at a sufficient throughput for drug screeningThe Optopatch platform recently developed at Q State Biosciencescomprised of both engineered optogenetic proteinscustom microscopesand softwaremakes it possible to simultaneously stimulateblue lightand recordred lightelectrical activity from around one hundred neurons with one millisecond temporal resolutionsingle cell spatial resolution and high signal to noisePatterned blue light can be used to stimulate one or a larger subset of neurons while recording from all of the synaptic partnersUsing a custom engineered channelrhodopsin for stimulation in combination with red fluorescent sensors of voltagecalcium and pH targeted to preand post synaptic locationswe will develop a set of assays that span synaptic functionFurthermorewe will probe shortand long term synaptic plasticity using different stimulus regimesTo validate the assayswe will test know pharmacological modulators of synaptic machineryWe will also test for an in vitro phenotype for knockout of a post synaptic scaffolding proteinSHANKwhose loss of function has been implicated in ASD and schizophreniaWe will use both mouse and human iPSC based models of diseased neuronsThese optical toolswhich can scale to high throughputhave the potential to change the drug screening landscape for neurological disordersWe hope to open a new path to finding treatments for these devastating diseases