The Holder lab investigates the genetic and neurobiologic basis
of neurodevelopmental and neuropsychiatric disorders. 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.
By identifying genetic modifiers of protein stability, we aim to
identify therapeutic entry points for these disorders. Verifying a
physiologic role for genes identified through these screens will be
performed in animal models and iPSC-derived neurons from
Second, we are investigating 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 is using 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 that predispose to bipolar disorder in families. We
then propose to use animal models of these changes to validate
their role in neuropsychiatric disorders.