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.
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.