Model Systems Research
Principal Investigator: Dr. Bryen Jordan
We recently identified patients around the world harboring monogenic deletions of the ANKS1B gene with confirmed haploinsufficiency. Affected individuals present with a spectrum of neurodevelopmental phenotypes, including autism and speech and motor deficits. The long-term goal of the proposed research is to define the mechanisms underlying AnkSyd and to identify therapeutic targets. ANKS1B encodes for AIDA-1, a brain-specific protein that we have shown is enriched at neuronal synapses and regulates N-methyl-d-aspartate receptors (NMDARs) subunit composition and NMDAR-dependent synaptic plasticity.
Our immediate goals are to test the hypothesis that NMDAR dysfunction contributes to AnkSyd. Toward this purpose, we have generated induced pluripotent stem cells (iPSCs) and neurons from patients and unaffected family members, as well as a transgenic mouse model that displays behavioral correlates of patient phenotypes. Our objectives are to test NMDAR function in patient neurons, elucidate mechanisms linking AIDA-1 to NMDAR function, and identify disease-relevant molecular pathways underlying AnkSyd using a discovery-based approach. Our work has direct implications for human health and our understanding of synaptic function.
Cerebellum and Autism
Principal Investigator: Dr. Kamran Khodakhah
The cerebellum has been implicated in a number of neurocognitive disorders such as autism , schizophrenia, and addiction. However, how it contributes to these disorders is not understood. In this proposal we explore whether the cerebellum sends direct excitatory projections to the ventral tegmental area (VTA), one of the brain regions that processes and encodes reward, and to the hypothalamus, a region implicated in social behavior. Using a combination of anatomical, functional (electrophysiology combined with selective optogenetic activation of cerebellar pathways), and behavioral studies we test the hypothesis that direct cerebellar projections to these two brain structures may be the substrate through which the cerebellum influences social behavior under physiological and pathological conditions. Defects in cerebellar modulation of the VTA and hypothalamus may explain, at least in part, how the cerebellum might contribute to disorders such as autism and schizophrenia. Thus, accomplishment of the goals set would not only advance our understanding of the non-motor functions of the cerebellum but may provide clues regarding the pathophysiology of a number of neurocognitive disorders.
Principal Investigator: Dr. Peri Kurshan
Altered synaptic structure and function is a hallmark of disorders characterized by Intellectual Disability (ID). Despite the identification of particular synaptic proteins that have been implicated in ID and Autism, the mechanisms by which defects in synaptic proteins lead to synapse dysfunction, and ultimately to neurodevelopmental disorders, are still largely unknown. We are studying two synaptic proteins in particular, the synaptic cell adhesion molecule Neurexin, which is highly associated with Autism, and the presynaptic voltage-gated calcium channel, a mutation in which was recently discovered in an IDDRC patient. We use the nematode C. elegans as a model system because of its highly tractable genetics and ease of experimental accessibility.
Neurexins are highly associated with Autism although their precise role at the synapse is increasingly being questioned. Long thought to be initiators of synapse development, recent evidence suggests they modulate synaptic function and plasticity, perhaps through interactions with other presynaptic proteins. However, neurexin’s intracellular presynaptic partners are largely unknown. To gain a better understanding of neurexin’s presynaptic signaling pathways we are undertaking an in vivo proximity ligation and proteomics approach using the newly-developed TurboID method.
We have recently shown that neurexin clusters calcium channels at the presynaptic terminal. Presynaptic calcium channels encoded by the CACNA1A gene in humans underlie synaptic transmission at nerve terminals and CACNA1A mutations have recently been linked to intellectual impairment and Autism. An IDDRC patient who presents with global developmental disabilities, seizures and ataxia was recently found to harbor a mutation in CACNA1A. The mutated residue is within a highly conserved region of the protein and is itself conserved all the way down to invertebrates, including C. elegans. Using CRISPR/Cas9 we have created C. elegans transgenic worms harboring this mutation and are using this strain to characterize the effects of this mutation on calcium channel localization and function, as well as on synaptic morphology and organismal behavior.