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Isabel Pérez-Otaño Activity-dependent removal of non-conventional NMDARs from the synapse.

Abstract :


I
n recent years, it has become clear that alterations in excitatory neurotransmission are major factors in the development of neuropsychiatric and neurological diseases. The goal of my laboratory is to identify cellular and molecular links between glutamate receptor function and brain development and pathology.
Our research combines in vitro and in vivo approaches to uncover components of the molecular machinery that can be manipulated to alter glutamatergic transmission, and thereby interfere with signaling pathways that lead to disease. At the molecular and cell biological level, we are investigating the trafficking and regulation of specific subtypes of glutamate receptors that are involved in synaptic plasticity, neuronal death, and functional disorders of the nervous system such as schizophrenia. We are particularly interested in how neurons use specific trafficking patterns to change their receptor complement, and how these processes influence synapse formation/maturation and ultimately shape synaptic connectivity. At the whole animal level, we are using genetic tools to recapitulate defects in receptor trafficking in vivo in order to generate novel mouse models of neural disease.
The maturation of excitatory synapses involves a change in the properties of NMDA receptor-mediated synaptic currents during development. A key step in this process is the regulated switch between "developmental" and "mature" forms of the NMDA receptor, and requires the elimination of "immature" versions of the NMDA receptor containing subunits such as NR2B or NR3A.
Here I will discuss a novel cell biological mechanism that seems to mediate an important aspect of this maturation. Our previous studies showed that the inhibitory NR3A subunit is a principal regulator of the NMDA component of synaptic trasnmission, especially at immature synapses. Inclusion of NR3A causes the formation of ‘non-conventional’ NMDA-activated channels with low calcium permeability and limited sensitivity to magnesium block, thereby modifying the two kinetic propertis thought to be key to NMDA receptor function. We have recenly identified elements of the intracellular machinery that control where and when NR3A-containing NMDA receptors are expressed in neurons. This cell biological control involves adaptor proteins that bind specifically to NR3A and work in the precise temporal and spatial fashion that is required for a mechanism operating at a synapse-specific level.
Our current work is directed to elucidate how the experience-dependent removal of NR3A-containing NMDA receptors drives changes in synaptic plasticity that in turn influence excitatory synapse maturation.

Selected publications

Pérez-Otaño, I., Plomann, M., Heinemann, S.F., Lo, D.C., and Ehlers, M.D.,
Activity-dependent synaptic removal of NMDA receptors mediated by the endocytic adaptor PACSIN/syndapin 1,
Nature Neuroscience (in review).
Pérez-Otaño, I. and Ehlers, M.D.,
NMDAR trafficking in metaplasticity and synaptic homeostasis,
Trends in Neuroscience, 28, 229-238 (2005)..
Pérez-Otaño, I. and Ehlers, M.D.,
Learning from NMDAR trafficking: clues to the development and maturation of glutamatergic synapses,
Neurosignals, 13, 175-189 (2004).
Wong, H, Liu, X., Matos, M.F., Chan, S.F., Pérez-Otaño, I., Boysen, M., Cui, J., Nakanishi, N., Trimmer,J.S., Jones, E.G., Lipton, S.A. and Sucher, N.J.,
The temporal and anatomical expression of NMDA receptor subunit NR3A in the mammalian brain,
J. Comp. Neurology 450, 303-17 (2002).
Vissel, B., Royle, G.A., Christie, B.R., Schiffer, H.H., Ghetti, A., Tritto, T., Pérez-Otaño, I., Radcliffe, RA,Seamans, J., Sejnowski, T., Wehner, J.M., Collins, A.C., O’Gorman, S. and Heinemann, S.F.,
The role of RNA editing of kainate receptors in synaptic plasticity and seizures.
Neuron 29, 217-227 (2001).

Christophe Mulle