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New mechanism uncovered that controls nerve cell communication during learning and long-term memory

14 February 2017

A new publication in Nature Neuroscience presents the findings of Professor Jeremy Henley, School of Biochemistry, and collaborators at the University of Central Lancashire.

The main finding of our work is the discovery of the new mechanism of long-term potentiation (LTP), the form of synaptic plasticity by which the connections between neurons are enhanced to allow cognition and underpin learning and memory.

Most excitatory synapses in the brain use the neurotransmitter glutamate, which acts at three types of ligand-gated ion channel receptors; AMPA receptors, NMDA receptors and kainate receptors. It has long been known that a core mechanism of LTP is that certain patterns of NMDA receptor activation cause the recruitment of AMPA receptors to the postsynaptic membrane and increase the efficiency of synaptic transmission.

We have discovered a new type of LTP that is induced by kainate receptors rather than NMDA receptors. Transient kainate receptor activation recruits AMPA receptors to the postsynaptic membrane and also increases the size of the synapse. Surprisingly, these actions are not due to the ion channel properties of kainate receptors but are mediated by a metabotropic G-protein pathway requiring PKC phosphorylation, PLC activation and raised intracellular calcium levels. This ‘non-cononical’ signalling of kainate receptors is fairly well accepted in the field but it remains puzzling because the receptors don’t have a 7-transmembrane structure, nor do they have obvious G-protein binding domains.

Increased understanding the interplay between kainate receptors and AMPA receptors should provide new information about how synaptic activity is orchestrated and neuronal circuits formed and maintained. For example, we now have preliminary data that different patterns of kainate receptor activation can decrease synaptic AMPARs leading to long-term depression, another critical aspect of learning and memory.

As importantly, these results open new avenues to explore the roles of kainate receptors in diseases, including epilepsy and neurodegenerative diseases like Alzheimer’s, which are characterized by dysfunctional synaptic plasticity and synapse loss. This new pathway could provide new therapeutic targets to delay, reduce or even prevent these devastating diseases.

Further information

Metabotropic action of postsynaptic kainate receptors triggers hippocampal LTP’  by Milos M. Petrovic, Silvia Viana da Silva, James P. Clement, Ladislav Vyklicky, Christophe Mulle, Inmaculada M González-González, and Jeremy M. Henley is published in Nature Neuroscience.

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