Main research topics of the research group of Jakob von Engelhardt

We work on the mechanisms of neuronal communication. A main focus is the molecular and electrophysiological foundation of synaptic transmission and of information processing in neuronal networks of the central nervous system (CNS). Another focus is the understanding of the pathophysiology of diseases of the nervous system such as Alzheimer’s disease, Parkinsons’s disease, Huntington’s disease, schizophrenia and epilepsy.

Glutamate receptors

 

Glutamate, the main excitatory transmitter in the vertebrate CNS, binds to AMPA-, NMDA- or kainate-receptors. We investigate how different types of AMPA receptors influence fast synaptic transmission. Furthermore, we aim to understand the role of NMDA receptor subtypes in synaptic plasticity, learning and memory as well as in the pathophysiology of CNS diseases.

 

 

AMPA receptor complexes and auxiliary subuits

 

AMPA receptors are tetramers containing different combinations of the four subunits GluA1-4. Native AMPA receptor complexes comprise in addition auxiliary subunits such as the proteins of the TARP, CKAMP, cornichon families and GSG1L. AMPA receptor trafficking, subcellular localization and function depends on the composition of the AMPA receptor complex. AMPA receptor function differs between synapse and cell type, which can be explained by developmental, cell-type, brain region and subcellular differences in AMPA receptor composition. A main focus of our research group is the investigation of the role of different auxiliary subunits in AMPA receptor function. Auxiliary subunits of the CKAMP family (CKAMP39, CKAMP44, CKAMP52, and CKAMP59) regulate the number of AMPA receptors on the cell surface and in synapses. In addition, CKAMPs modulate AMPA receptor gating. For example, AMPA receptors that interact with CKAMP44 recover very slowly from desensitization. Using in vitro and in vivo electrophysiology, we showed that the influence of auxiliary subunits on AMPA receptor gating is relevant for synaptic function and neuronal activity in the hippocampus, visual system (dLGN) and olfactory bulb. We are currently investigating the role of auxiliary subunits information processing and neuronal network activity in different brain areas using in vivo tetrode recordings and 2P-microscopy.

Role of NMDA receptors in synapse physiology and pathophysiology.

 

NMDA receptor activation induces synaptic plasticity (long term potentiation and depression), which is thought to by one of the underlying mechanisms of learning and memory. However, overactivation of NMDA receptors can induce excitotoxicity via excessive influx of Ca2+. NMDA receptors are tetramers containing two GluN1 and two of the four different GluN2 subunits (GluN2A-D). NDMA receptor function depends on their subunit composition. NMDA receptor composition differs between cell types of different brain areas. These differences may explain the diverse roles of NDMA receptors in synaptic plasticity and pathophysiology of neurodegenerative diseases such as Alzheimer’s and Huntington’s disease. Using electrophysiological techniques, molecular biology, in situ hybridization and immunohistochemistry, we are investigating the functional expression profiles of NDMA receptors in brain areas such as hippocampus, cortex and striatum and their contribution to the pathophysiology of neurodegenerative diseases.

 

 

Genetic and molecular cause of familial neurodegenerative diseases

 

To identify the genetic cause of monogenic neurodegenerative diseases, we use whole genome sequencing. Our main focus in this project is to identify and novel molecules that are implicated pathophysiology of neurodegenerative diseases. Functional characterization of the molecules are done using cell culture systems and knockout mouse models. In our functional analyses, we focus mainly on synaptic proteins.