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Nicoll Lab Research

 

The Nicoll lab is interested in the molecular basis of synaptic transmission and synaptic plasticity. To explore this, we rely on electrophysiology, molecular biology, and genetics to dissect the role of crucial post- and trans-synaptic proteins. As our main model system, we are focused on the rodent hippocampus, specifically the CA3 to CA1 synapse, though we also study from the CA3 and dentate gyrus region of the hippocampus, from the cerebellum, and from heterologous cells.

Here is a sampling of some of the current projects in the lab:

 

- AMPA receptor trafficking and LTP -

AMPA receptors (AMPAR) drive most of the fast, excitatory synaptic transmission in the brain, and their trafficking into and out of the synapse is a major mechanism regulating synaptic strength. We are interested in how AMPA receptors are trafficked, and how their trafficking is regulated during synaptic plasticity. To study AMPA receptors, we have developed a single-cell molecular replacement strategy where we can exert complete control over the complement of expressed AMPA receptors in individual hippocampal neurons. Using this strategy, we are systematically dissecting the AMPA receptor to identify domains and regions crucial for proper trafficking and function of the receptor.

 

- AMPAR auxiliary subunits -

In neurons, functional AMPARs exist in complexes with a variety of other transmembrane proteins, called auxiliary subunits. These auxiliary subunits are crucial for the proper trafficking and biophysical properties of AMPARs. The first AMPAR auxiliary subunits identified were the TARP (transmembrane AMPA receptor regulatory protein) family, whose impact on the trafficking, kinetics, and pharmacological properties of AMPARs has been a major focus of research in the lab. We continue to study the role that different TARP subunits play in synaptic transmission and plasticity in the hippocampus and cerebellum, and have expanded our focus to the rapidly expanding array of other transmembrane auxiliary subunits, including Cornichon (CNIH) and SynDIG proteins.

 

- NMDA receptor trafficking -

N-methyl-d-aspartate receptors (NMDARs) are ionotropic glutamate receptors that play crucial roles in neurodevelopment and synaptic plasticity. NMDARs are tetramers containing two obligatory GluN1 subunits and two GluN2 subunits, with GluN2A and GluN2B being the predominant subunits in the mammalian forebrain. The functional properties of NMDARs, including the decay kinetics of NMDARs currents, are largely determined by their GluN2 subunit composition, and the expression pattern of GluN2 subunits is spatially and developmentally regulated. At most forebrain excitatory synapses, GluN2B-containing NMDARs predominate early in development and are gradually replaced or supplemented by ‘mature’ GluN2A-containing receptors.

Until recently the dogma in the field was that NMDARs were relatively immobile fixed structures. However, we and others have found a remarkable plasticity of synaptic NMDAR that involves the activity-dependent switching of subunits. For example, we recently demonstrated that at immature synapses, a neuronal stimulation protocol used to induce synaptic plasticity was able to rapidly, within seconds, switch the synaptic NMDAR composition from predominantly GluN2B-containing to predominately GluN2A-containing. These results added to a growing literature indicating that the expression, trafficking, synaptic localization and functioning of different NMDAR subtypes are under dynamic cellular control. However, the mechanisms involved in modulating synaptic NMDARs trafficking and function are poorly understood. Using conditional knock-out mice and an innovating molecular replacement strategy, we are dissecting the mechanisms involved in the synaptic targeting and trafficking of NMDARs.

 

- MAGUK scaffolding of the PSD -

Proper synaptic localization of glutamate receptors requires that they associate with the complex network of signaling and scaffolding molecules known as the post-synaptic density (PSD). Multiple lines of evidence demonstrate that scaffolding proteins localized to the PSD play an active role in regulating the basal levels of synaptic glutamatergic receptors. The major protein family implicated in synaptic glutamate receptor localization is the four-member membrane-associated guanylyl kinase (MAGUK) family: PSD-93, PSD-95, SAP97, and SAP102.

The MAGUKs are cytoplasmic proteins that are highly enriched at the PSD. They bind glutamate receptors and proteins responsible for the enlargement and maturation of the synapse via PDZ binding domains and link these proteins to the cytoplasmic scaffold using C-terminal SH3 and GK domains. They have been shown to play an instructive role in the localization of synaptic AMPA-type glutamate receptors. Ongoing research in the Nicoll Lab focuses on the mechanisms underlying MAGUK-dependent localization of glutamate receptors at hippocampal synapses.

 

- Neuroligins in the formation and maintenance of synaptic transmission -


- LGI1 regulation of synaptic transmission -