Healthy synapse function relies on the adequate presence of mitochondria. The heightened energy utilization of activity-dependent processes supporting long-term potentiation (LTP) places even greater a demand on mitochondria and, indeed, mitochondrial dysfunction is implicated in many neuropsychiatric disorders including autism and schizophrenia. Although the mechanisms that support dendritic mitochondrial reorganization are unclear, a key process impacting mitochondrial distribution is mitochondrial fission. Thus, two central questions that remain are whether LTP induction impacts mitochondrial fission, and whether mitochondrial fission is required for LTP. Mitochondrial fission is regulated by a GTPase, dynamin-related protein 1 (Drp1), which itself is tightly regulated by phosphorylation. Intriguingly, CaMK1? and calcineurin, both required for LTP induction, also increase Drp1 recruitment to mitochondria and mitochondrial fission by regulating Drp1 phosphorylation. Yet, despite these indications, the link between LTP and mitochondrial fission remains unknown. Driven by this curiosity, I used a protocol to chemically induce LTP (chemLTP) to test whether LTP induction increases mitochondrial fission. My preliminary data show a rapid and transient burst of mitochondrial fission after chemLTP stimulation, in addition to robust and sustained canonical changes to dendritic spine morphology. Together, these observations lead me to hypothesize that LTP requires an increase in dendritic mitochondrial fission via direct regulation of Drp1 function. I will use a diverse arsenal of confocal and super-resolution microscopy, molecular perturbations, and biochemistry techniques to determine the relationship between LTP, Drp1 function, and mitochondrial fission by addressing three specific aims. First, I will determine whether LTP requires an increase in dendritic mitochondrial fission. I will confirm and extend my preliminary findings by testing whether the fission increase is NMDAR-dependent by blocking NDMARs. To test whether induction of LTP requires fission, I will block fission by expressing a Drp1 dominant negative mutant, and will measure properties of dendritic spines, synapses, and mitochondrial fission after chemLTP stimulation. Second, I will determine whether chemLTP stimulation changes recruitment or mobility of Drp1 oligomers on mitochondria using confocal microscopy particle tracking. My preliminary data suggest that Drp1 puncta become drastically less mobile prior to inducing fission and I will measure the effect of chemLTP stimulation on this mobility. To measure whether mobility of isolated Drp1 molecules on mitochondria is altered during LTP, I will use single molecule tracking photoactivated localization microscopy (sptPALM). Third, I will determine whether LTP induction requires phosphorylation of Drp1 via Western blots with phospho-specific antibodies, and by measuring fission and dendritic spine properties in the presence of phospho-mimetic and phospho-null Drp1 constructs. In sum, these Aims will greatly extend our understanding of mitochondrial fission in neurons, and will elucidate the unexplored relationship between mitochondrial fission and synaptic potentiation.

Public Health Relevance

My findings are designed to improve our understanding of how essential molecular components of mitochondrial physiology come together to enable normal function and potentiation of the excitatory synapse, the sine qua non of brain function. Furthermore, they will provide new assays for probing the underlying causes of synaptic dysfunction in mitochondrial, neurodegenerative, and neuropsychiatric diseases. Better knowledge of these causes will shape or reshape the approach to prevention and treatment of various neurological and neuropsychiatric diseases such as autism spectrum disorder, schizophrenia, Huntington?s, Alzheimer?s, and Parkinson?s.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Driscoll, Jamie
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Maryland Baltimore
Schools of Medicine
United States
Zip Code