Molecular Mechanisms of Synaptic Plasticity

I aim to mechanistically understand how assemblies of synaptic proteins contribute to synaptic plasticity in health and disease

Synaptic transmission presents the main mode of communication in the brain. It can adapt to demand, a process termed synaptic plasticity, which adds greatly to the information processing capacity of the brain. In particular, because malfunction at the synaptic level can have strong impact on circuity and brain function, I have been interested in understanding the mechanisms by which plasticity is achieved. Synaptic dysfunctions (synaptopathies) underlie various disorders and teach us how synaptic transmission and plasticity act, while shedding light on potential treatment solutions. This area I will focus on.

Postsynaptic ligand-gated ion channels. Glutamate receptors, in particular the AMPA-type receptors, are key in adapting transmission of excitatory synapses in the brain. The life of this receptor in a neuron is highly regulated and over twenty different transiently interacting proteins are now known to be involved in synthesis, trafficking, mobility and modulation of these receptors. I like to put a main effort in understanding how these proteins act, their specific functions, and the potential they have as target for intervening with plasticity. Focus is, and will be, on the functional analysis of the Shisa family of proteins and their contribution to AMPAR plasticity.

This work is performed by several people. Remco Klaassen is currently investigating the Shisa family. Sophie van der Spek addresses additional complexity of the glutamate receptor, also in the context of Alzheimer disease. This work is done together with the neuroproteomics team of Ka Wan Li and the psychiatric disorder team of Sabine Spijker.

Miguel Lozano, Pim van Nierop, Ka Wan Li,Remco Klaassen, Guus, Frank Koopmans, Andrea Ganz, Roel vd Schors, Iryna Paliukhovich en Sophie van der Spek.

Synaptopathies. Several disorders are brought about by dysfunction in synaptic proteins. Human genetic data, in particular in the last decennium, has provided a wealth of new synaptic gene candidates. A major effort is necessary to bridge the gap between genetic evidence and biological understanding. New possibilities are at hand by using human (patient)-derived neurons and characterizing their molecular and cellular phenotypes. In addition, I will contribute to dissecting synaptopathies by using animal models that mimic specific gene mutations in the human brain.

Synaptic organization. One of the challenges of the coming years will be to understand how synaptic proteins are organized in larger networks and how synapses adapt on the long-term. It will be of interest to measure (synaptic) adaptations during healthy aging and development of cognitive disorders of the human brain. My interest lies specifically in the area of dementia (FTD, AD), where due to excellent collaboration at campus new possibilities are present to molecularly identify disease mechanisms.

1: Klaassen RV, Stroeder J, Coussen F, Hafner AS, Petersen JD, Renancio C, Schmitz LJ, Normand E, Lodder JC, Rotaru DC, Rao-Ruiz P, Spijker S, Mansvelder HD, Choquet D, Smit AB. Shisa6 traps AMPA receptors at postsynaptic sites and prevents their desensitization during synaptic activity. Nat Commun. 2016 Mar 2;7:10682. doi: 10.1038/ncomms10682. PMID: 26931375

2: Karataeva AR, Klaassen RV, Ströder J, Ruiperez-Alonso M, Hjorth JJ, van Nierop P, Spijker S, Mansvelder HD, Smit AB. C-terminal interactors of the AMPA receptor auxiliary subunit Shisa9. PLoS One. 2014 Feb 3;9(2):e87360. dos: 10.1371/journal.pone.0087360. PubMed PMID: 24498314

3: Li KW, Chen N, Smit AB. Interaction proteomics of the AMPA receptor: towards identification of receptor sub-complexes. Amino Acids. 2013 May;44(5):1247-51. doi: 10.1007/s00726-013-1461-9. Review. PubMed PMID: 23344883.

4 : von Engelhardt J, Mack V, Sprengel R, Kavenstock N, Li KW, Stern-Bach Y, Smit
AB, Seeburg PH, Monyer H. CKAMP44: a brain-specific protein attenuating short-term synaptic plasticity in the dentate gyrus. Science. 2010 Mar 19;327(5972):1518-22. doi: 10.1126/science.1184178. PubMed PMID: 20185686.

5: Li KW, Klemmer P, Smit AB. Interaction proteomics of synapse protein complexes. Anal Bioanal Chem. 2010 Aug;397(8):3195-202. toi: 10.1007/s00216-010-3658-z. Review. PubMed PMID: 20361179

6: Hondius DC, van Nierop P, Li KW, Hoozemans JJ, van der Schors RC, van Haastert
ES, van der Vies SM, Rozemuller AJ, Smit AB. Profiling the human hippocampal
proteome at all pathologic stages of Alzheimer’s disease. Alzheimers Dement. 2016
Jun;12(6):654-68. doi: 10.1016/j.jalz.2015.11.002. PubMed PMID: 26772638.