More info regarding the lab projects will be available soon on my lab webpage.

Molecular and functional neurobiology of learning and memory is the research interest of the lab

In contemporary neuroscience memory is discriminated into immediate, short-term and long term forms. Immediate and short term memories have a limited capacity and last only for a period of several seconds to a minute. On the contrary, long-term memory has nearly unlimited capability to store information for unlimited duration. Long-term memory is divided into declarative (explicit) and non-declarative (implicit) types. Declarative memory includes facts whereas non-declarative memory refers to acquisition of skills and habits. These two types of memory are formed by different brain structures, hippocampus along with other medial temporal lobe structures with further consolidation in the neocortex are related to declarative whereas neostriatum and cerebellum mediate non-declarative memory mechanisms. In addition, amygdale has been shown to mediate emotional memory and being involved in memory consolidation. Declarative memory is divided into episodic memory (the personally experienced event specific to a particular context such as time and place) and semantic memory referred to facts taken independent of the context in which they were learned.

Memory formation mechanisms include multiple processes of signal transduction related protein phosphorylation and de novo protein synthesis via regulation both on transcriptional and translational levels. Protein de novo synthesis is absolutely necessary for long term memory formation, however there is no well-defined time frame differentiating protein synthesis dependent and independent memories. Studies conducted in invertebrates show that associative olfactory conditioning in Drosophila can last over 24 hours in the absence of protein synthesis, whereas in Aplysia increases in postsynaptic responsiveness in motor neurons depend on rapid protein synthesis only after 10 min. Overall, de novo protein synthesis requires activation of multiple signaling pathways leading to signaling factor translocation into the nucleus and regulation of transcription factors, e.g. cAMP-PKA pathways activation leading to phosphorylation of CREB in the nucleus, in addition with cross-talk mechanisms with CaMKII, CaMKIV and ERK pathways found to be crucial for the memory consolidation. Beyond regulation of transcription factors such as CREB, involvement of other TFs in the long term memory formation was reported e.g. for AP1, Zif268 and NF-kB. Moreover, several kinases, e.g. ERK1/2, p38 MAPK RS6K responsible for histone phosphorylation and in parallel being crucial for the long term memory formation led to the suggestion that chromatin remodeling is also important in memory formation. Regulation on the translation level was shown also to be crucial for long lasting changes in synaptic strength and memory formation. Dephosphorylation of translation factor eIF2 correlates with late-LTP and long term memory formation. Another regulator of translation process, mTOR, was shown to affect memory consolidation in mammals and long term plasticity in Aplysia. Effect of phosphorylation of another translational regulator eIF4E was also shown to affect LTP and mGLUR-LTD. Overall, during the last two decades multiple protein components and their modification have been implicated in memory formation, however despite widespread use of modern high throughput methods in different fields of neurobiology, combined application of proteomics and genomics in study of learning and memory processes is very limited.

Our research interest at the current stage includes the following points

What are the signaling molecules, which deliver signal to the nuclei of neurons and how are they modified? Here we are employing proteomics including mass spectrometry and protein microchip approaches with further target analysis of the identified candidates

What is transcriptional and protein de novo synthesis response involved in memory formation? Here we employ gene microarray and deep sequencing analysis for transcript detection and proteomic approach to identify de novo synthesized proteins.

What is transcriptional and protein de novo synthesis response involved in memory formation? Here we employ gene microarray and deep sequencing analysis for transcript detection and proteomic approach to identify de novo synthesized proteins.

How the signaling molecules regulate protein synthesis elaborated in the memory formation? Here we employ in silico analysis approach to delineate major protein signaling networks with further target specific analysis via up- and downregulation of the corresponding genes in vivo. We will elaborate behavioral, electrophysiological and morphological study for this reason

How does signal delivery affect the memory formation? Here we test involvement of neuronal transport system via targeted in vivo effect of up- and downregulation of transport proteins genes on the memory formation process.

What are molecular mechanisms elaborating aging related memory impairment? This project will extensively exploit in vivo experiments with proteomic and genomic approaches together with behavioral and electrophysiological studies

Which changes do appear in the memory formation molecular networks upon stress and how the latter affects the memory formation process? What is the mechanism linking post-traumatic stress disorder and memory? This project will elaborate combination of conventional neurobiological research in PTSD mouse model together with high-throughput study and electrophysiology.

How does transient brain ischemia impact on spatial memory? This project will elaborate animal model of brain ischemia with subsequent behavioral, electrophysiological and high-throughput study.

During our study, we will take advantage of the experimental paradigms related to the spatial memory as the research model system.

Excellence, motivation and open mind are mandatory pre-requisites for everyone interested to adjoin. The projects are available for students (Ph.D., M.Sc.) and post-doctoral research fellows.

In case you experience difficult to find these reviews, please contact me.

Fili O*, Michaelevski I*, Bledi Y, Chikvashvili D, Singer-Lahat D, Boshwitz H, Linial M, Lotan I. Direct interaction of a brain voltage-gated K+ channel with syntaxin 1A: functional impact on channel gating. J Neurosci 2001 Mar 15; 21(6):1964-74.

Michaelevski I, Chikvashvili D, Tsuk S, Fili O, Lohse MJ, Singer-Lahat D, Lotan I. Modulation of a brain voltage-gated K channel by syntaxin 1A requires the physical interaction of G beta/gamma with the channel. J Biol Chem 2002 Sep 20;277(38):34909-17.

Michaelevski I, Chikvashvili D, Tsuk S, Singer-Lahat D, Kang Y, Linial M, Gaisano HY, Fili O, Lotan I. Direct interaction of target SNAREs with the Kv2.1 channel. Modal regulation of channel activation and inactivation gating. J Biol Chem. 2003 Sep 5;278(36):34320-30.

Tsuk S*, Michaelevski I*, Bentley GN, Joho RH, Chikvashvili D, Lotan I Kv2.1 channel activation and inactivation is influenced by physical interactions of both syntaxin 1A and the t-SNARE complex with the C-terminus of the channel. Mol Pharmacol. 2005 Feb; 67(2): 480-8

Wolf-Goldberg T*, Michaelevski I*, Sheu L, Gaisano HY, Chikvashvili D, Lotan I Target soluble N-ethylmaleimide-sensitive factor attachment protein receptors (t-SNAREs) differently regulate activation and inactivation gating of Kv2.2 and Kv2.1: Implications on pancreatic islet cell Kv channels. Mol Pharmacol. 2006 Sep;70(3):818-28.

Michaelevski I, Korngreen A, Lotan I. Interaction of syntaxin with a single Kv1.1 channel: a possible mechanism for modulating neuronal excitability. Pflugers Arch. 2007 Jun;454(3):477-94.

Post-Doc and Research Associate

Perlson E, Michaelevski I, Kowalsman N, Ben-Yaakov K, Shaked M, Seger R, Eisenstein M, Fainzilber M. Vimentin binding to phosphorylated erk sterically hinders enzymatic dephosphorylation of the kinase.J Mol Biol. 2006 Dec 15;364(5):938-44.

Lvov A, Chikvashvili D, Michaelevski I, Lotan I. VAMP2 interacts directly with the N terminus of Kv2.1 to enhance channel inactivation. Pflugers Arch. 2008 Sep; 456(6):1121-36.

Tsuk S, Lvov A, Michaelevski I, Chikvashvili D, Lotan I. Formation of the full SNARE complex eliminates interactions of its individual protein components with the Kv2.1 channel. Biochemistry. 2008 Aug 12;47(32):8342-9.

Feinshreiber L, Chikvashvili D, Michaelevski I, Lotan I. Syntaxin modulates Kv1.1 through dual action on channel surface expression and conductance. Biochemistry. 2009 May 19;48(19):4109-14.

Lvov A, Greitzer D, Chikvashvili D, Tsuk S, Berlin S, Lotan I& and Michaelevski I& Rearrangement in the relative orientation of cytoplasmic domains induced by a membrane anchored protein – mediated Kv channel gating modulation. J Biol Chem 2009, 284(41):28276-91.

Rishal I, Michaelevski I, Shinder V, Medzihradszky K.F, Burlingame A.L, & Fainzilber M Axoplasm Isolation from Peripheral Nerve. Developmental Neurobiology, 2010 Feb; 70(2):126-33.

Michaelevski I&, Medzihradszky KF, Burlingame,AL & Fainzilber M&: Axonal transport proteomics reveals mobilization translation machinery to the lesion site in injured sciatic nerve. Mol. Cell. Proteomics. 2010 May 9(5):976-87;

Michaelevski I Segal-Ruder Y, Rozenbaum M, Medzihradszky K.F, Shalem O, Coppola G, Horn-Saban S, Ben-Yaakov K, Dagan S.Y, Rishal I, Geshwind D.H, Pilpel Y, Burlingame A.L, & Fainzilber M. Signaling to Transcription Networks in the Neuronal Retrograde Injury response. Science Signaling. 2010 Jun 13; 3(130):ra53: 1-10

Michaelevski I, Eisenstein M, Sharon M: Gas-phase compaction and unfolding of protein structures. Analytical Chemistry 2010, 82(22): 9484-91

Reviews

Kirshenbaum N, Michaelevski I, Sharon M. Analyzing Large Protein Complexes by Structural Mass Spectrometry. Journal of Visualized Experiments, 2010; ePublish: http://www.jove.com/index/Details.stp?ID=1954  ;Review

Michaelevski I, Kirshenbaum N, Sharon M. T-wave Ion Mobility-mass Spectrometry: Basic Experimental Procedures for Protein Complex Analysis. Journal of Visualized Experiments, 2010; ePublish: http://www.jove.com/index/details.stp?id=1985 ;Review

Book chapter