Kainate Receptors: A Potential Target for Novel Cerebellar Therapies

The Institute of Neurosciences (IN), a collaborative center of the Miguel Hernández University (UMH) of Elche and the Spanish National Research Council (CSIC) is leading a study in Tokyo, Japan, in conjunction with Keio University, which highlights the critical role one of the glutamate receptors plays in the proper functioning of the cerebellum's synapses.

The study details the molecular process by which kainate receptors serve as "scaffolds" that maintain the structure of connections between neurons in addition to their role as synaptic receptors in a work that was just published in the journal Cell Reports.

The research provides promising avenues for future therapeutic applications and allows the design of new synaptic connectors using particular combinations of kainate receptor subunits.

The points of connection known as synapses are where neurons connect to exchange information. A neurotransmitter is released by the presynaptic neuron and picked up by the postsynaptic neuron for this communication to happen.

Glutamate receptors, which are neurotransmitters involved in various processes of the central nervous system, have been the subject of extensive research at the IN's Synaptic Physiology laboratory headed by CSIC researcher Juan Lerma. In particular, kainate receptors, one of the three families of glutamate receptors that mediate communication between neurons, have been the subject of extensive study.

For many years, we have tried to find out what the function of kainate receptors is in synaptic physiology and brain pathologies.”

Juan Lerma,  Spanish National Research Council

Understanding the roles of these proteins in synaptic communication—which, when disrupted, results in a variety of neurological and neuropsychiatric disorders—has been greatly aided by his laboratory's efforts. The GluK4 protein is one of the five subunits that make up kainate receptors.

This team of IN researchers had previously identified the role that this protein can play when it is overexpressed in pathologies like anxiety, depression, and autism. Additionally, they showed that individuals with Down syndrome have triplicate levels of the GluK1 protein and that these decompensated levels are what cause the spatial memory deficits that these patients experience.

Moreover, over the years, the Michisuke Yuzaki-led laboratory in the Department of Neurophysiology at the Keio University School of Medicine in Tokyo has investigated the formation of synapses in the cerebellum and found that an interaction between the C1ql1 and Gai3 proteins takes place in this area to facilitate synaptic formation.

However, the new study's findings contradict this theory by showing that synapses cannot form if both proteins do not interact with kainate receptors:

By combining our experience and knowledge in this new collaboration, we have been able to completely redefine synapse formation in the cerebellum.”

Michisuke Yuzaki, Laboratory Lead, Department of Neurophysiology, School of Medicine, Keio University

The experts verified that the interaction supporting synaptic transmission between climbing fibers and these neurons requires the expression of GluK4, which is found in cerebellar Purkinje neurons.

The researchers genetically altered the expression of these proteins in mouse models to verify. Studies conducted in the laboratories of Yuzaki in Tokyo and Lerma in Alicante demonstrate that when either of these kainate receptors is suppressed, it has a significant impact on the cerebellum's synaptic plasticity, which is essential for motor learning. Both receptors are required for the formation of synapses.

Impacts of Synaptic Plasticity Failure

Ana Valero Paternain, Study Co-First Author, explained: “Synaptic plasticity is the brain’s ability to form connections and modulate them depending on its needs. When plasticity fails, serious motor defects occur.”

In the laboratory, we have verified that when the number of synapses is reduced, mice are not able to learn motor behaviors.”

Wataru Kakegawa, Study Co-First Author, Universidad Miguel Hernandez De Elche

Replicated synaptic connectors based on similar proteins have demonstrated potential in repairing impaired synapses in rodent models of spinal cord injuries and Alzheimer's disease. As a result, the findings open up encouraging possibilities for further therapeutic uses.