Associate Professor, Research, Neurobiology & Anatomy
Synaptic Vesicle Proteins As Regulators Of Neurotransmitter Release
The properly regulated secretion of neurotransmitters in the brain is essential for normal functioning of the brain. Many neurological and psychiatric diseases show a lack or an imbalance of neurotransmitters with severe consequences. Parkinson’s disease, Alzheimer’s disease, epilepsy, schizophrenia and depression are just a few examples of such diseases.
The study of the mechanism of synaptic neurotransmitter secretion is important for the understanding, diagnosis and the potential treatment of these diseases. The release of neurotransmitters in the brain occurs mainly via synaptic vesicle exocytosis. Synaptic vesicle proteins are thought to be important elements in this process. However the functional analysis of these proteins has been extremely difficult due to the lack of functional assays and in vitro systems. My lab studies the involvement of synaptic proteins in neuronal function by using genetic approaches. The generation of mice mutated in genes coding for synaptic proteins allows the analysis of protein function in a whole animal and can produce valuable models for neurological diseases. In previous studies we generated mutant mice using gene targeting by homologous recombination in embryonic stem cells. The effect of the inactivation of genes coding for different synaptic vesicle proteins was studied. The ablation of some of these genes leads to disturbance of the normal regulated synaptic transmission. This demonstrates that some synaptic vesicle proteins are involved in the regulation of the efficiency of synaptic connections.
We are using biochemical, physiological and genetic methods to study the molecular basic of this process. Furthermore we are generating new mice lines that are deficient in other synaptic proteins to understand their biological function. The analysis of these mice with different methods should help to clarify the role of the mutated proteins in synaptic transmission.
- Janz, R, Südhof, TC. (1999) SV2C is a synaptic vesicle protein with an unusually restricted localization: Anatomy of a synaptic vesicle protein family. Neuroscience, Vol. 94, 1279-1290.
- Janz, R, Südhof, TC, Hammer, RE, Uni, V, Siegelbaum, S, Bolshakov, VY. (1999) Essential roles in synaptic plasticity for synaptogyrin I and synaptophysin I. Neuron, Vol. 24, 687-700.
- Janz, R, Goda, Y, Geppert, M, Missler, M, Südhof, TC. (1999) SV2A and SV2B function as redundant Ca2+ regulators in neurotransmitter release. Neuron, Vol. 24, 1003-1016.
- Wang, MM, Janz, R, Belizaire, R, Frishman, LJ, Sherry, DM. (2003) Differential distribution and developmental expression of synaptic vesicle protein 2 isoforms in the mouse retina. Journal of Comparative Neurology, Vol. 460, 106-122.
- Belizaire, R, Komanduri, SF, Wooten, K, Thaller, C, Janz, R. (2004) Characterization of Synaptogyrin 3 as a new synaptic vesicle protein. Journal of Comparative Neurology, Vol. 470, 266-281.
- Lazzell, DR, Belizaire, R, Thakur, P, Sherry, DM, Janz, R. (2004) SV2B regulates Synaptotagmin 1 by direct interaction. Journal of Biological Chemistry, Vol. 279, 52124-52131.
- Dong, M, Yeh, F, Tepp, WH, Dean, C, Johnson, EA, Janz, R, Chapman, ER. (2006) SV2 is the protein receptor for botulinum neurotoxin A. Science, 28 April 2006: 592-596.
- Curtis LB, Doneske B, Liu X, Thaller C, McNew JA, Janz R. (2008) Syntaxin 3b is a t-SNARE specific for ribbon synapses of the retina. J Comp Neurol. Oct 10;510(5):550-9. PubMed PMID: 18683220; PubMed Central PMCID: PMC2893228.
- Wan QF, Zhou ZY, Thakur P, Vila A, Sherry DM, Janz R, Heidelberger R. (2010) SV2 acts via presynaptic calcium to regulate neurotransmitter release. Neuron. Jun 24;66(6):884-95.
- Curtis L, Datta P, Liu X, Bogdanova N, Heidelberger R, Janz R. (2010) Syntaxin 3B is essential for the exocytosis of synaptic vesicles in ribbon synapses of the retina. Neuroscience. Mar 31;166(3):832-41.