Kendal Broadie, Ph.D.

Stevenson Professor of Neurobiology

Stevenson Professor of Neurobiology

Research Description

What are the genetic and molecular mechanisms underlying coordinated movement, integrated behavior, cognition, learning and memory? How does the nervous system circuitry underlying these behaviors develop? How is information relayed rapidly and accurately within neural circuits? How are neural circuits modified by experience to optimize behavior? How do these mechanisms go awry in inherited neurological diseases and age-related neurological decline? These questions center around the common themes of information transfer and information storage in cells of the nervous system. My long-term interest has been to understand the fundamental principles of nervous system development, function and use-dependent plasticity by applying systematic genetic analyses to address these questions.

The primary focus of my laboratory is on the synapse, the specialized intercellular junction which functions as the communication link between neurons, and between neurons and muscle. Chemical synapses mediate the vast majority of communication in the nervous system and exhibit plastic properties underlying the behavioral and cognitive malleability of the brain. Our experimental approach is to use a combination of forward genetics, reverse genetics and functional genomics to identify synaptic genes, generate mutants and then assay mutant phenotypes to elucidate the function of normal synaptic gene products. Our laboratory uses this strategy to investigate three closely related questions: 1) How do synapses develop?, 2) How do synapses function? and 3) How do synapses maintain adaptive plasticity?

Synaptic development involves specifying and constructing the intercellular communication link. The developmental program specifies synaptic partnerships and aligns presynaptic signal release with postsynaptic receptors. The mature synapse translates electrical information into chemical information and back again. This conversion requires mechanisms coupling action potential to vesicle fusion, receptor activation and downstream signaling. Synaptic plasticity is the key to nervous system adaptability, including higher cognitive functions. Synaptic structure and function by use, to modulate communication either transiently (learning) or permanently (memory). We screen directly for genetic mutants defective in learning/memory and then assay the roles of the mutant genes at the synapse.

A primary interest is to develop models of human neurological diseases linked to inherited synaptic dysfunction. We study disease states ranging from movement disorders to intellectual disabilities. One focus is Fragile X syndrome (FXS), the most common heritable disease resulting in cognitive impairment and autism spectrum disorder (ASD). Multiple lines of evidence show that FXS is caused by defects in synaptic development and plasticity due to inappropriate translational regulation. We are employing a range of complementary behavioral, electrophysiological, imaging and molecular genetic approaches to study this disease state and test treatments. We are particularly interested in activity-dependent mechanisms during the critical period of synaptic development in central brain circuits.

Our approach to the neuronal synapse is multi-disciplinary and requires the marriage of many traditionally distinct fields. Our strategy involves classic geneticists, molecular biologists, developmental cell biologists, electrophysiologists and behavior scientists. Most members of our research group combine two or more of these approaches in their studies, and also collaborate with others having their own specialized skills. In the long term, we hope that our work will lead to greatly improved understanding of nervous system development, function and plasticity including the molecular mechanisms of neural circuit formation, integrated neural communication, higher brain functions such as learning and memory, and treatments for synaptic dysfunction arising in inherited neurological disease states.

Selected Publications