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Functions of the N-terminal and C-terminal domains of glutamate receptors (Ole Paulsen)

Supervisor: Ole Paulsen

Ionotropic glutamate receptors mediate synaptic excitation in the brain. The AMPA receptor is responsible for fast excitatory synaptic transmission. It consists of four subunits, each with a large extracellular N-terminal domain (NTD) whose function is largely unknown. The NMDA receptor contributes to a slower component of synaptic transmission and is important for synaptic plasticity. It also has four subunits, and the intracellular C-terminal domain (CTD) binds to molecular components leading to synaptic plasticity. Projects in this area will explore possible functions of the NTD and CTD in excitatory synaptic transmission and plasticity.

Using a combination of patch-clamp recording and imaging techniques, the location and function of AMPA and NMDA receptors will be investigated in primary neuronal culture as well as acute brain slices from animals expressing AMPA and/or NMDA receptor subunits lacking the NTD or CTD or with NTDs and CTDs with different mutations. In particular, using bio-orthogonal chemistry, un-natural amino acids will be targeted to these molecular domains, which then later can be used to localise the receptor (by adding a fluorescent tag) or control the activity (by adding a photosensitive element). In this way, we hope to be able to localise and manipulate NMDA receptors and recently inserted AMPA receptors following induction of long-term potentiation (LTP) in order to identify and control the potentiated state of synapses, i.e. enable toggling a synapse between its potentiated and depotentiated states.

Parts of this project will be done in collaboration with Dr Ingo Greger at the LMB.

Relevant references

Banerjee A, Larsen RS, Philpot BD and Paulsen O (2016) Roles of presynaptic NMDA receptors in neurotransmission and plasticity. Trend Neurosci 39: 26-39.

Kohl MM, Shipton OA, Deacon RM, Rawlins JNP, Deisseroth K and Paulsen O (2011) Hemisphere-specific optogenetic stimulation reveals left-right asymmetry of hippocampal plasticity. Nat Neurosci 14: 1413-1415.

Shipton OA and Paulsen O (2013) GluN2A and GluN2B subunit-containing NMDA receptors in hippocampal plasticity. Philos Trans B 369: 20130163.

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