The Holder lab investigates neurodevelopmental and neuropsychiatric disorders' genetic and neurobiological basis. There are currently three main projects in the Holder Lab.
First, we use cell-based screens to identify genetic modifiers of two synaptic proteins, SHANK3 and SynGAP. Mutations in the SHANK3 and SYNGAP1 genes cause severe neurodevelopmental disorders associated with intellectual disability, autism, and epilepsy. Both are typically caused by de novo mutations which result in haploinsufficiency. We aim to identify therapeutic entry points for these disorders by identifying genetic modifiers of protein stability. Verifying a physiological role for genes identified through these screens will be performed in patients' animal models and iPSC-derived neurons.
Second, we investigate the neuronal and circuit dysfunction responsible for the phenotypes associated with SHANK3 Duplication Syndrome. We are currently focusing on the role of striatal neurons in behavioral abnormalities of mice modeling this disorder. Our lab uses Cre-LoxP and Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to map the neurons responsible for these behavioral abnormalities.
Third, we are investigating the role of genetic variants on bipolar disorder. We use next-generation sequencing to identify genetic changes predisposing to bipolar disorder in families. We then propose to use animal models of these changes to validate their role in neuropsychiatric disorders.