Leonard Kaczmarek, PhD

My laboratory investigates how changes in the intrinsic excitability of neurons result in changes in behavior, learning and memory. Specifically, we study the role of potassium channels, as well as other classes of ion channels. The Kaczmarek laboratory was the first to demonstrate directly, using purified enzymes, that excitability of neurons is regulated by cyclic AMP-dependent protein kinase, protein kinase C and tyrosine phosphatases. Our group has isolated the genes for over fourteen novel ion channels and was the first to identify the “two-pore” family of potassium channels. Among the channels that our group cloned and characterized are the Kv3.1b channel, which is required for high-frequency firing in auditory brainstem neurons, the K_Ca3.1 Ca²⁺-activated channel, and the Slack and Slick genes that underlie Na⁺-activated K⁺ channels in these and many other neurons. Our work was the first to show directly that rapid changes in the phosphorylation state of ion channels (Kv3.1b) and in the synthesis of new channels occur in vivo in response to changes in an animal’s auditory environment.

Over the past decade we have found that the gating of ion channels directly influences cytoplasmic signaling pathways necessary for neuronal function. One example is the interaction of the Kv3.3 channel with the cell-survival protein Hax-1, a protein-protein interaction that triggers actin nucleation required for endocytosis of synaptic vesicles at fast-firing synapses. Another is the finding that the Slack protein interacts with the Fragile X Mental Retardation Protein FMRP, and that gating of the channel triggers initiation of mRNA translation by recruiting FMRP away from the initiation complex. Most recently our laboratory has collaborated with clinicians and geneticists to develop antisense oligonucleotide treatments mutations in Slack channel, which produce very severe intellectual disability in humans and these treatments are currently being used in infants.

I have been very fortunate to have many exceptionally talented pre- and postdoctoral trainees, as well as MD-PhD. students in my laboratory. Thirty-two of the students and postdocs from my laboratory have gone on to hold tenure-track faculty positions at major institutions including Brown University, Yale University, UCSF, UCSD, Vanderbilt and many more.