The overarching goal of our research program is to identify and characterize cellular and molecular processes, driven by changes in electrical activity and calcium signaling, that underlie the generation of distinct types of neurons during the development of the mammalian brain. My lab employs a variety of approaches to explore how immature, undifferentiated neural progenitor cells integrate intrinsic and extrinsic signals to commit to specific neuronal fates, such as the different types of excitatory cells inhabiting the cerebral cortex. These techniques include in utero electroporation, neuroanatomical tracing, voltage and calcium imaging, biochemical and genetic tools, RNA sequencing and single cell analyses.
Normal neurogenesis, the process by which new neurons are born and integrated into the developing brain, encompasses a series of precisely timed events. These cellular processes are essential both for generating neurons of the correct type in the appropriate place and time, and for ensuring that these new neurons properly connect to one another to form circuits that control behavior. When any of these processes go awry, the consequences on brain function can manifest as neurodevelopmental disorders like mental retardation, learning disabilities, and autism. In the normal developing brain, newborn neurons first arise from the division of less specialized cells known as neural stem or progenitor cells. During this process of differentiation, a young neuron acquires its fate, which includes a number of individual properties such as its gene expression, migration to its final position, its patterns of electrical activity, and its axonal projections. The acquisition of neuronal identity is in part regulated by subtype-specific transcriptional programs. Electrical activity and downstream calcium signaling cascades have also been shown to regulate processes involved in the development of specific brain circuits. The interaction of extrinsic electrical signals with the intrinsic regulation of the transcriptional programs specifying neuronal differentiation, however, remains unclear. The work in my lab is thus aimed at understanding two fundamental questions:
- What are the specific mechanisms through which electrical activity in early brain development gets converted into long term changes in progenitor cells to regulate commitment to a specific neuronal identity?
- How do altered patterns of electrical activity in developing brain circuits disrupt neuronal differentiation to give rise to psychiatric disorders?
Our research will allow us to draw conclusions about the role of specific ion channels and calcium signaling proteins in molecular and cellular events that regulate the development of specific neuronal subtypes. Understanding how young neurons in the normal brain choose their fate will also allow us to understand how and why that choice can go wrong to give rise to neurodevelopmental disorders. Mutations in calcium channels and related calcium signaling proteins have been associated with a number of neuropsychiatric disorders, including autism, schizophrenia and bipolar disorder, making them a particularly interesting target for investigation in the context of normal and abnormal cortical development.