The Project
Regulation of glutamate receptors during plasticity and learning.
Winner
Casper Hoogenraad
Erasmus Medical Centre
Department of Neuroscience
Rotterdam, The Netherlands
www.neuro.nl
Since 2002, Dutchman Casper Hoogenraad, 32 years old, has been a postdoctoral fellow at the Picower Center for Learning and Memory / Howard Hughes Medical Institute at the Massachusetts Institute of Technology, Cambridge, MA, USA. He graduated in 1994 with a B.Sc in Biochemistry from the Hogeschool Rotterdam in The Netherlands, followed by an M.Sc in Biology from Utrecht University, The Netherlands, in 1996, and a Ph.D in Molecular Biology from Erasmus University, Rotterdam, The Netherlands, in 2001. He is widely published, with over 20 research papers and more than 340 citations.
Award
€1,199,196
Project Description
The overall aim of this project is to elucidate the mechanisms underlying hippocampal and cerebellar synaptic plasticity(*) and to determine how basis cellular mechanisms contribute to learning. We will take a multidisciplinary approach of biochemistry, molecular biology, neuronal cell biology, electrophysiology and behavioural assays. Central to this approach is a genome-wide RNA interference (RNAi) screen in hippocampal pyramidal neurons and cerebellar Purkinje cells. We will use a cDNA-derived short interfering (si)RNA library to screen for genes required for glutamate receptor functioning. We will specifically focus on the genes responsible for the delivery of glutamate receptors to and from the postsynaptic membrane.
The project has three key objectiv
- To perform an unbiased genome-wide loss of function screen to identify novel regulators of glutamate receptor trafficking. We propose to make restriction-enzyme generated siRNAs (REGS), a simple, effective and inexpensive strategy to construct a siRNA library that encompasses all expressed genes. We will investigate the genes that are essential for trafficking of glutamate receptors in response to synaptic activity by individually depleting all the target sequences in neurons, including those with unknown function and differentially spliced transcripts.
- To investigate the molecular function of glutamate receptor-adaptor-motor protein complexes. We propose to immunopurify and identify all the components of the glutamate receptor interacting protein (GRIP) adaptor complex by mass spectrometry to discover the possible cargo molecules that are transported in neurons by this complex.
- To look at postsynaptic mechanisms underlying hippocampal and cerebellar plasticity and learning. Based on the results obtained from the above studies we propose to make "knock-down" transgenic mice by lentiviral technology to study the molecular mechanism of glutamate receptor trafficking in vivo.
Understanding the precise molecular mechanisms underlying plasticity will increase our insight in memory formation in the brain. Such knowledge will be relevant for understanding neurological and psychiatric disorders and may provide new strategies for improving treatment of these disorders.
(*) Definition - synaptic plasticity:
The term synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse. It can involve changing the postsynaptic neuron's excitability (the chance that it will fire after a given level of stimulus) in response to the amount of stimulus it has received in the past. Synaptic plasticity is part of the Hebbian theory about the neurochemical foundations of memory and learning. (Source: Wikipedia)
