DZNE-Junior Research Group Synaptic Signalling and Neurodegeneration
PD Dr. Jakob von Engelhardt
Our group investigates glutamatergic synaptic transmission in the hippocampus and cortex. We are particularly interested in what role different glutamate receptors (AMPA- and NMDA-receptors) and glutamate receptor-interacting proteins play in physiological and pathophysiological processes. AMPA receptors mediate most of the fast excitatory transmission in the central nervous system. NMDA receptors are important for synaptic plasticity and thus for learning and memory. In addition, excessive activation of NMDA receptors is detrimental for neurons (excitotoxicity) and contributes to the pathophysiology of brain diseases such as stroke and neurodegenerative diseases.
1.) Mechanisms of Amyloid ß pathology:
One of the hallmarks of Alzheimer's disease is the accumulation of amyloid beta-peptide (Aß) in the brain and its deposition as plaques. However, the current prevailing view is that soluble oligomeric Aß is one of the main mediators of Alzheimer neurotoxicity, rather than the plaques. There are indications that glutamate receptors play a role in Aß-mediated neurotoxicity. We will use glutamate receptor transgenic mice to investigate the influence of this interaction on the physiology and anatomy of hippocampal and cortical neurons.
2.) Regulation of synaptic communication via AMPA-receptor interacting proteins:
Precise control of AMPA receptor number and localization on the cell membrane regulates synaptic strength and is thus of great importance for all cognitive processes. AMPA-receptor interacting proteins (TARPs, CKAMP44, cornichons and SynDig1) regulate receptor localization and function. We will use heterologous expression systems and transgenic mice to analyze the influence of those proteins on the electrophysiological properties and localization of AMPA-receptors.
Khodosevich K, Jacobi E, Farrow P, Schulmann A, Rusu A, Zhang L, Sprengel R, Monyer H, and von EngelhardtJ. (2014) Coexpressed Auxiliary Subunits Exhibit Distinct Modulatory Profiles on AMPA Receptor Function. Neuron 83: 601-15
von Engelhardt J, Mack V, Sprengel R, Kavenstock N, Li KW, Stern-Bach Y, Smit AB, Seeburg PH, Monyer H (2010) CKAMP44: a brain-specific protein attenuating short-term synaptic plasticity in the dentate gyrus. Science 327:1518-1522.
Khodosevich K, Lazarini F, von Engelhardt J, Kaneko H, Lledo PM, Monyer H. Connective Tissue Growth Factor Regulates Interneuron Survival and Information Processing in the Olfactory Bulb. Neuron. 2013 Sep 18;79(6):1136-51.
von Engelhardt J, Doganci B, Jensen V, Hvalby O, Gongrich C, Taylor A, Barkus C, Sanderson DJ, Rawlins JN, Seeburg PH, Bannerman DM, Monyer H (2008) Contribution of hippocampal and extra-hippocampal NR2B-containing NMDA receptors to performance on spatial learning tasks. Neuron 60:846-860.