Graduate Student Spotlight:
Graduate student, Rob Kozol (Dallman Lab), explores the genetic basis of Autism Spectrum Disorders
My research focuses on how genetic mutations contribute to sensory and motor deficits in Autism Spectrum Disorders (ASD). Although the core diagnostic features of ASD include communication and social deficits, the vast majority of individuals with ASD live with simultaneous conditions, or comorbidities, such as epilepsy and poor motor control. These sensory and motor comorbidities could be the result of changes at several organismal levels. At the circuit level neuronal signals could be imbalanced while at the cellular level, neuronal extensions such as dendrites and axons may be impaired. Therefore we seek to determine how ASD mutations affect these various levels to produce sensory and motor deficits.
To apply this multi-level model we use mutated zebrafish that have conserved vertebrate genetics and development. We can create mutations in zebrafish versions of ASD genes and easily observe the anatomy and activity of neurons due to the transparency of larval zebrafish. In addition zebrafish have stereotyped sensory and motor behaviors that can be tested using high-throughput behavioral screens. These attributes contribute to a top-down model starting with behavioral screens for sensory and motor impairments that can then be explored at the whole brain, circuit and cell levels.
We are currently applying this top-down model using zebrafish with mutations in the ASD gene SHANK3. SHANK3 is mutated in ~1% of individuals with ASD and the majority of these individuals suffer from various comorbidities, including sleep disturbances and epilepsy. Therefore to study sleep disturbances zebrafish are monitored for frequency of movement (a corollary for wake-sleep) from morning to night. If mutants exhibit sleep disturbances, then we look for changes in protein expression of phosphorylated ERK (pERK) that corresponds with brain activity. Finally, when a local brain circuits show a change in pERK expression we ask whether or not that group of neurons exhibit changes in the anatomical state, or when accessible, changes in their electrophysiology. It is our hope that this top-down model will pinpoint the neuronal basis for sensory and motor comorbidities. Importantly these neurons and networks may be similar or different those associated with social deficits in individuals with SHANK3 mutations and may perhaps provide new therapeutic targets that have not been identified in other SHANK3 animal models.
For example to study disrupted sleeping patterns mutant and wild-type zebrafish are monitored for frequency of movement (a corollary for sleep-wake cycle) from morning to night. If mutants show changes in sleep-wake, then we look for changes in a protein that is expressed in active neurons, phosphorylated ERK (pERK). These changes could be in large brain regions, subregions or specific groups of neurons.