Nerve terminals in the brain must
synthesize ATP on demand to sustain
function. Here, Ashrafi, de Juan-Sanz,
et al. show that axonal mitochondria use
the brain-specific MCU regulator MICU3
to allow efficient Ca2+ uptake in order to
accelerate ATP production.

The focus of Dr. Tim Ryan’s lab is the study of the molecular basis of synaptic transmission in the mammalian brain. Dr.Ryan’s primary interests lie in understanding the molecular basis of synaptic performance.

They use biophysical tools to examine synapse function. These tools provide single synapse measurements of exocytosis, endocytosis, action potential wave forms, calcium fluxes as well as the concentration of key metabolites. The brain is acutely sensitive to metabolic compromise. They showed recently that nerve terminals represent one of the key loci of this vulnerability (Cell 2014). These studies opened up several key questions the Ryan lab is currently pursuing about synaptic metabolism. How much ATP do different processes at synapses consume? What are the biochemical rules in play to synthesize ATP in response to activity? What are the biochemical reasons synapses are so vulnerable?

Dr. Timothy Ryan was trained as a physicist, with a master’s degree in experimental particle physics from McGill University. He then studied protein mobility on cell surfaces and signal transduction with Dr. Watt Webb (Cornell University) for his PhD. With his background in physics and biochemistry, he then joined Dr. Stephen Smith (Stanford) to investigate synaptic vesicle recycling. Over the years, his work has been recognized through distinctions such as The Alfred P. Sloan Fellow in Neuroscience, McNight technological innovations in Neuroscience, NIH Javitz Neurosceince award, and Siegel Family Award for outstanding biomedical research. Now, Dr. Ryan is a Rockefeller/Sloan-Kettering/Cornell Tri-Institutional Professor at the Weill Cornell Medical College and an HHMI Senior Fellow at the Janelia Research Campus in Ashburn Virginia. His lab works in unravelling how synaptic transmission is controlled. They develop novel quantitative optical tools that give us information about “hidden variables” i.e., aspects of cell biology and physiology that play crucial roles in determining synaptic properties but have not been readily explored. For example: how local bioenergetics and metabolism impact synaptic functioning; how the local action potential waveform is; what the role of the endoplasmic reticulum in the axon is. Dr. Ryan will elaborate during his talk, for which he has kindly provided a synopsis: “The brain is a metabolically vulnerable organ: interrupting the fuel supply leads to a rapid and drastic decline in brain function. By developing an approach to measure the concentration of ATP in nerve terminals, we showed that synapses represent one of the likely loci of the brain’s vulnerability. We discovered that synapses to not store sufficient ATP molecules to carry out function when activity increases and must therefore synthesize ATP on demand locally. In the last several years we have worked out some of the mechanisms that link activity to ATP production: blocking these regulatory pathways leads to rapid block of synapse function as if they were provided no fuel. I will describe our current work unravelling both the mechanistic aspects of this regulation as well as new clues we have obtained regarding the bio-energetic costs of different aspects of presynaptic function.”

The cost of thinking and not thinking: metabolic control of synapses.

Talk on May 11th 4-5pm PST

Tim Ryan. PhD

Weill Cornell Medical School, New York, NY

The human brain is a metabolically vulnerable organ. A decrease in blood glucose of only a factor of 2 leads to rapid manifestations of neurological symptoms including delirium and coma. This sensitivity to hypometabolic conditions implies that fundamentally neurons themselves do not tolerate brief interruptions in fuel supply.  To investigate the molecular underpinnings of the metabolic control of neuron function we developed reductionist approaches in the last several years to examine the interface of metabolic and synaptic function. Our work has shown that nerve terminals are likely loci of the brain’s metabolic vulnerability, as they do not store sufficient ATP to sustain function and must synthesize this critical biochemical currency on-demand in response to electrical activity. Our most recent work now shows that in addition, nerve terminals have very high-resting metabolic rates, that are independent of electrical activity. This high resting synaptic metabolism in turn determines, in part, synaptic performance in hypometabolic states.

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