NR3 · Role of NMDA receptor endocytic trafficking in the development of neural circuitry
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2006-01-02 → 2008-01-01
- EU contribution
- €80,000
- Participants
- 1
- Scheme
- IRG
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Results in brief
Final Activity Report Summary - NR3 (Role of NMDA receptor endocytic trafficking in the development of neural circuitry)
This research project was awarded to study the contribution of local trafficking mechanisms to the exchange of synaptic N-methyl-D-aspartate (NMDA) type glutamate receptors (NMDARs) and, thus, to the development of mature neuronal networks. The main focus was to study how the removal or replacement of immature non-conventional NMDARs containing the NR3A subunit would contribute to synapse maturation and consolidation of neuronal networks, and what were the underlying mechanisms. We progressed in two main directions: 1. We firstly identified different endocytic pathways followed by NR3A subunits in immature and mature neurons. Briefly, NR3A endocytosis required a tyrosine-based signal located in the intracellular C-terminus of NR3A which directed the receptor for recycling. This pathway was dominant in immature neurons, which lacked the F-Bar protein PACSIN1. In mature neurons, PACSIN1 selectively favoured endocytosis of NR3A-containing receptors and inhibited their recycling, potentially favouring the developmental elimination of NR3A-containing receptors and allowing for their replacement with mature NMDAR types (Pérez-Otaño et al. Nature Neuroscience, 9, 611 2006; Saint-Michel et al. manuscript in preparation). 2. Using transgenic mice with impaired developmental downregulation of NR3A-containing NMDARs, we demonstrated the critical importance of eliminating juvenile NR3A-containing NMDARs for proper synapse maturation and, more surprisingly, for mature circuits to achieve the ability to consolidate memories. Our results strongly suggested that NR3A down-regulation was a key mechanism that enabled young brains to acquire the plastic ability which was required for shaping and hard-wiring the brain, potentially by signalling the beginning of critical periods of postnatal development (Roberts et al., submitted). This role was only possible because of the sharp and striking timing of NR3A expression in the brain, being expressed only a few weeks after birth, and because of its unique ability to inhibit NMDAR transmission.
Data: CORDIS, © European Union
Project objective
NMDARs play essential roles in the development and refinement of neuronal connections by contributing to the maturation and stabilization of synapses and dendritic spines. A key step regulating synaptic stabilization is the transition from developmental to mature NMDAR subtypes during a critical postnatal period of brain development. However, little is known about the molecular mechanisms for removing or replacing NMDARs at the synapse.This proposal will investigate molecular/cell biological mechanisms that mediate the synaptic exchange of NMDARs, and the role they play in establishing appropriate synaptic connectivity. Our previous studies indicate that a principal regulator of NMDARs at immature synapses is the inhibitory NR3A subunit. Specifically, NR3A d irects for synaptic removal of NMDARs via rapid internalization. NR3A-mediated internalization is tightly regulated as it requires both activity and the recruitment of a neuronal-specific adaptor, PACSIN1/syndapin1. Our working hypothesis is that rapid dow nregulation of NMDARs-containing NR3A from synapses provide a critical signal that allows enhanced localization of mature NMDARs at synapses and thus stabilizes neuronal circuits during development. The experiments in this proposal are designed to test thi s model directly by analyzing how changes in NR3A expression affect the development of correct numbers of synapses and dendritic spines. The proposal represents a three-tiered approach to understand the role of specific pathways of NMDAR endocytic traffic king, starting with the basic characterization of a novel cell biological mechanism in vitro, the manipulation of molecular elements of this pathway to study its importance for the proper development of synaptic connections, and using a complementary genet ic approach to determine the extent to which inclusion of NR3A in the NMDAR complex controls spine morphogenesis and its possible causative role in neurodevelopmental disorders such as schizophenia.
Original text from CORDIS.
Participants
- FUNDACION PARA LA INVESTIGACION MEDICA APLICADA · PAMPLONACoordinatorCity levelSpain
Links
Data: CORDIS, © European Union