Our laboratory studies how synapses form between neurons in the cerebral cortex and how these mechanisms go awry in neurodevelopment diseases, such as autism.
Our primary approach is to use live imaging to observe the process of synaptogenesis, but we complement our imaging with electrophysiological, biochemical and molecular genetic approaches.
Synapse Formation: The neural circuits that govern perception and behavior are composed of networks of neurons that communicate with one another via synapses. As our brains develop, the roughly 10-20 billion neurons that comprise the human cerebral cortex are presented with the enormous and complex task of forming trillions of synapses.
Understanding cortical synaptogenesis and circuit assembly is essential for understanding normal brain function.
Errors in circuit development are linked to pathogenesis of neurodevelopmental diseases such as autism spectrum disorders (ASD), intellectual disability, epilepsy and schizophrenia. Understanding the causes of these diseases is of tremendous importance since they affect a huge number of people. In order to determine how circuit development is disrupted in such diseases, it is necessary to understand the fundamental molecular and cellular mechanisms of synapse formation.
Synaptogenesis is also important for repair after brain injury, integration of stem cell-derived neurons into neuronal networks, and treatment of disorders like Alzheimer's Disease in which synapse loss occurs prior to diagnosis.
Our current projects are focused on:
1. Regulation of presynaptic development by NMDA receptors: One project in the lab aims to determine the role of glutamate and presynaptic NMDA receptor signaling during synapse formation, with an emphasis on presynaptic development.
Glutamate is released from neocortical neurons prior to synapse formation, but how this released glutamate contributes to synapse formation is not yet clear. Similarly, many developing neocortical pyramidal neurons express presynaptic NMDA receptors, but their function during synapse development has not been studied.
We are addressing this through both in vitro and in vivo studies.
2. ASD-associated mutations in NR2B: Another project in the lab is focused on understanding how ASD-associated mutations in the NMDA receptor subunit NR2B contribute to pathogenesis of ASD.
We have replicated ASD mutations in rodents and are currently examining their effects of NMDA receptor function and trafficking and on circuit development.
3. In vivo imaging of synapse development: Another project in the lab is focused on imaging of synapse development in the cortex of living mice. For this, we are imaging through cranial windows and labeling a particular subset of synapses by using either virally-mediated expression of fluroscently-tagged synaptic proteins or transfection via in utero electroporation.
We are examining the basic mechanisms of synapse formation and the effects of NMDA receptor activity on synapse development in vivo.