Schizophrenia (SCZ) is a chronic, severe and disabling mental illness that affects 1% of the population, yet has no effective treatment. Antipsychotic medications can interrupt positive symptoms such as hallucinations in a subset of individuals, but have little impact on negative (social withdrawn) or cognitive symptoms. Tremendous progress in human genetics in the past few years has revealed polygenic risk factors underlying schizophrenia. Our best chance to develop the next generation therapeutics for schizophrenia relies on our ability to discover and validate novel biological risk factors implicated by the emerging SCZ genetics. CACNA1I is a risk gene identified by GWAS, and encode the α1 functional core of the CaV3.3 voltage-gated calcium channels. Emerging evidences connect the function of CaV3.3 with a few clinical observations in the schizophrenia patients including sleep spindle deficits. We hypothesize that impaired CaV3.3 plays a role in mediating SCZ risk, and it represents a potential novel target for schizophrenia. Here, we propose to utilize a primary HTS screen and a cascade of secondary physiological and cellular assays to identify positive and negative modulators that regulate CaV3.3 function with high specificity. By combining HTS, appropriate secondary screens, along with subsequent medicinal chemistry optimization, this multidisciplinary effort is expected to yield a panel of incisive chemical probes to dissect the expanding biological function of CaV3.3 in neurobiology and schizophrenia disease mechanism. 1