Senior Scientist, Vollum Institute
Paul Brehm received his degree in zoology from the University of Wisconsin before entering the PhD program at UCLA where he trained with James Morin in marine biology and bioluminescence. Postgraduate training with Roger Eckert at UCLA and Yoshi Kidokoro at The Salk Institute focused on calcium channels and synaptic transmission. The next 10 years were spent as an associate professor in the Department of Physiology at Tufts Medical School in Boston and summers at the Marine Biological Laboratory at Woods Hole. In 1990 Brehm moved to Stony Brook University in New York where he served as Professor of Neurobiology and Behavior before assuming a position as senior scientist at the Vollum in 2007.
Summary of current research
My lab is currently focused on several projects involving ion channels and synaptic transmission in vertebrate animal models. We continue to use paired in vivo patch clamp to explore poorly understood processes of synaptic transmission. Zebrafish is the only vertebrate preparation wherein paired motor neuron–target muscle patch clamp can be performed rendering it one of the most ideal model synapses. The transparency of the nervous system is also ideal for simultaneous use of optical activators and reporters of synaptic transmission. The many advantages offered by zebrafish over mouse have led to our recent discoveries of the calcium sensor synaptotagmin-7 as the master regulator of asynchronous transmitter release and identification of transmitter release zones that are tuned to different behavioral needs. Our ability to link synaptic plasticity and function to behavioral outputs renders it even more unique. Additionally, we have a large number of mutant lines that harbor defects in key synaptic components including receptor, calcium channels, and amino acid transporters. Along with providing new insights into the basics of neurotransmission, each of these mutants has been linked to specific human diseases such as slow channel syndrome, Lambert-Eaton syndrome, Episodic Apnea and Rapsyn deficient myasthenic syndrome. Finally, over the past few years we have generated a panel of transgenic fish lines expressing combinatorial genetically engineered indicators of calcium, vesicular exocytosis, and photo-activatable channelrhodopsin within the nervous system. This allows exquisitely sensitive testing the means through which recruitment of motor neurons, on the bases of both size and spinal topography, control finely tuned increases in the speed of swimming. Overall, we continue to delve more deeply into the detailed mechanisms through which the central nervous system can tune its output for individual behavioral tasks.
Wen H, Eckenstein K, Weihrauch V, Stigloher C, Brehm P. (2020) Primary and secondary motoneurons use different calcium channel types to control escape and swimming behaviors in zebrafish. Proc. Natl. Acad. Sci. USA 117:26429-26437.
Rakela B, Brehm P, Mandel G. (2018) Astrocytic modulation of excitatory synaptic signaling in a mouse model of Rett syndrome. Elife 7:e31629.
Wang WC, Brehm P. (2017) A gradient in synaptic strength and plasticity among motoneurons provides a peripheral mechanism for locomotor control. Curr. Biol. 27:415-422.
Wen H, Hubbard JM, Wang WC, Brehm P. (2016) Fatigue in rapsyn-deficient zebrafish reflects defective transmitter release. J. Neurosci. 36:10870-10882.
Wen H, McGinley MJ, Mandel G, Brehm P. (2016) Nonequivalent release sites govern synaptic depression. Proc. Natl. Acad. Sci. USA 113:E378-E386.
Naranjo D, Wen H, Brehm P. (2015) Zebrafish CaV2.1 calcium channels are tailored for fast synchronous neuromuscular transmission. Biophys. J. 108:578-584.
Wen H, Hubbard JM, Rakela B, Linhoff MW, Mandel G, Brehm P. (2013) Synchronous and asynchronous modes of synaptic transmission utilize different calcium sources. Elife 2:e01206.
Wen H, Linhoff MW, Hubbard JM, Nelson NR, Stensland D, Dallman J, Mandel G, Brehm P. (2013) Zebrafish calls for reinterpretation for the roles of P/Q calcium channels in neuromuscular transmission. J. Neurosci. 33:7384-7392.
Walogorsky M, Mongeon R, Wen H, Nelson NR, Urban JM, Ono F, Mandel G, Brehm P. (2012) Zebrafish model for congenital myasthenic syndrome reveals mechanisms causal to developmental recovery. Proc. Natl. Acad. Sci. USA 109:17711-17716.
Walogorsky M, Mongeon R, Wen H, Mandel G, Brehm P. (2012) Acetylcholine receptor gating in a zebrafish model for slow-channel syndrome. J. Neurosci. 32:7941-7948.
Wen H, Linhoff MW, McGinley MJ, Li GL, Corson GM, Mandel G, Brehm P. (2010) Distinct roles for two synaptotagmin isoforms in synchronous and asynchronous transmitter release at zebrafish neuromuscular junction. Proc. Natl. Acad. Sci. USA 107:13906-13911.
Luna VM, Brehm P. (2006) An electrically coupled network of skeletal muscle in zebrafish distributes synaptic current. J. Gen. Physiol. 128:89-102.
Li W, Ono F, Brehm P. (2003) Optical measurements of presynaptic release in mutant zebrafish lacking postsynaptic receptors. J. Neurosci. 23:10467-10474.
Ono F, Higashijima S, Shcherbatko A, Fetcho JR, Brehm P. (2001) Paralytic zebrafish lacking acetylcholine receptors fail to localize rapsyn clusters to the synapse. J.Neurosci. 21:5439-5448.
Naranjo D, Brehm P. (1993) Modal shifts in acetylcholine receptor channel gating confer subunit-dependent desensitization. Science 260:1811-1814.
Brehm P, Lechleiter J, Smith S, Dunlap K. (1989) Intercellular signaling as visualized by endogenous calcium-dependent bioluminescence. Neuron 3:191-198.
Henderson LP, Lechleiter JD, Brehm P. (1987) Single channel properties of newly synthesized acetylcholine receptors following denervation of mammalian skeletal muscle. J. Gen. Physiol. 89:999-1014.
Brehm P, Kullberg R. (1987) Acetylcholine receptor channels on adult mouse skeletal muscle are functionally identical in synaptic and nonsynaptic membrane. Proc. Natl. Acad. Sci. USA 84:2550-2554.
Dunlap K, Takeda K, Brehm P. (1987) Activation of a calcium-dependent photoprotein by chemical signalling through gap junctions. Nature 325:60-62.
Brehm P, Eckert R. (1978) Calcium entry leads to inactivation of calcium channel in Paramecium. Science 202:1203-1206.