Lonart, Gyorgy

Gyorgy Lonart
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Professor, Pathology and Anatomy

EVMS Directory Profile

research overview

My focus is synaptic transmission and mapping synaptic networks involved in fear, learning and sleep regulation. Pharmacological, physiological, and microscopic studies have made seminal contributions to our field, however the intracellular mechanisms that regulate neurotransmission remained mostly unknown until recently. Prior to becoming an EVMS faculty, I worked in the laboratory of T. C. Südhof, Nobel Prize in Medicine, 2013, to investigate the molecular mechanisms of neurotransmitter release. We have demonstrated that SNARE protein assembly-disassembly is dynamic, and that it is regulated by protein kinase C for many neurotransmitter types.

overview

1. The core of my work addresses mechanisms of synaptic transmission. Pharmacological, physiological, and electron microscopic studies have made seminal contributions to this field, however the intracellular mechanisms that regulate neurotransmission remained mostly unknown until recently. To elucidate intracellular/molecular mechanisms of neurotransmission, I joined the laboratory of T. C. Südhof as a junior faculty. Specifically, I investigated the molecular mechanisms that determine the size of the readily releasable pool of synaptic vesicles, and molecular targets for protein kinases in presynaptic plasticity. We have demonstrated that SNARE protein assembly-disassembly is dynamic, and is regulated by protein kinase C for many, but not all neurotransmitters. Assembly of a tripartite core complex from three SNARE protein components, synaptobrevin/VAMP, SNAP-25, and syntaxin is required for synaptic vesicle fusion. Our findings support the idea that core complex assembly represents an important point of regulation in neurotransmitter secretion and that presynaptic plasticity can operate at the step of prefusion by regulating the size of the readily releasable pool. In another series of studies, we found that Rab3 interacting molecule 1 alpha (RIM1α) is a target for protein kinase A. As an independent investigator, I extended these studies to downstream effectors of phospho-RIM1α and to another kinase ERK, a kinase that is also important for presynaptic plasticity. These studies helped mapping the molecular mechanisms that contribute to neurotransmitter release regulation, a field of investigation that was recognized by the Nobel Committee with a prize to T.C. Südhof in 2013.

a. Lonart, G., Südhof, T.C. (2000) Assembly of SNARE core complexes prior to neurotransmitter release sets the readily releasable pool of synaptic vesicles. J Biol Chem.275:27703-7.

b. Lonart, G., Schoch, S., Kaeser, P.S., Larkin, C.J., Südhof, T.C., Linden, D.J. (2003) Phosphorylation of RIM1alpha by PKA triggers presynaptic long-term potentiation at cerebellar parallel fiber synapses. Cell. 115:49-60.

c. Simsek-Duran, F., Linden, D.J., Lonart, G. (2004) Adapter protein 14-3-3 is required for a presynaptic form of LTP in the cerebellum. Nat Neurosci. 7:1296-8.

d. Simsek-Duran, F., Lonart, G. (2008) The role of RIM1alpha in BDNF-enhanced glutamate release. Neuropharmacology. 55:27-34.

2. To complement my molecular investigations above with a system approach, and to investigate whether the molecular mechanisms I studied influence behavior, I collaborated with my colleague L.D. Sanford on projects related to mechanisms of arousal, with an emphasis on sleep. Specifically, we addressed whether fear-induced changes in neurotransmitter systems in the amygdala may be associated with the longer-term changes in arousal. Our studies established the utility of an in vitro neurochemical assay for discriminating fear-induced alterations in norepinephrine and GABA release in multiple brain regions and demonstrated that fear-induced changes in neurotransmitter release can be detected in the amygdala. To investigate a molecular link between neurotransmitter release regulation and sleep, we investigated the role RIM1α. We demonstrated that mice lacking RIM1α (Rim1KO), a protein of the synaptic active zone, had less baseline rapid eye movement (REM) sleep. Also, exposure of these mice to an open ﬁeld or to a novel object induced more robust and longer lasting locomotion suggesting altered habituation. This difference in exploratory behavior correlated with genotype speciﬁc changes in REM and deregulated release of norepinephrine in the cortex and basal amygdala of the Rim1KO mice. As norepinephrine plays an important role in regulating arousal and REM sleep, our data suggested that noradrenergic deﬁciency in Rim1 KO animals impacts exploratory behavior and sleep regulation and contributes to impairments in learning.

a. Liu, X., Lonart, G., Sanford, L.D. (2007) Transient fear-induced alterations in evoked release of norepinephrine and GABA in amygdala slices. Brain Res. 20:1142:46-53.

b. Lonart, G., Tang, X., Simsek-Duran, F., Machida, M., Sanford, LD. (2008) The role of active zone protein Rab3 interacting molecule 1 alpha in the regulation of norepinephrine release, response to novelty, and sleep. Neuroscience. 154:821-31.