A determining mechanism for the formation of synapses in the cerebellum has been found

Synapses are the connection points established by neurons with each other to transmit information through nerve impulses. For this communication to occur, the presynaptic neuron releases a neurotransmitter and the postsynaptic neuron receives it.

The Institute of Neurosciences (IN), a joint centre of the Spanish National Research Council (CSIC) and the Miguel Hernández University (UMH) in Elche, Spain, has led, together with Keio University in Tokyo, Japan, a research project that has demonstrated the crucial role of one of the receptors of the neurotransmitter glutamate in the functioning of the synapses of the cerebellum.

In this new study, we have been able to describe the molecular mechanism by which kainate receptors not only act as synaptic receptors, but also as “scaffolds” that support the structure of connections between neurons. These findings pave the way for the design of new synaptic connectors using specific combinations of kainate receptor subunits, and offer promising avenues for future therapeutic applications.

The Synaptic Physiology laboratory headed by Juan Lerma, a CSIC researcher at the IN, has extensively investigated glutamate receptors, a neurotransmitter that intervenes in different processes of the central nervous system, and particularly those of kainate, one of the three families of glutamate receptors that mediate communication between neurons. “For many years, we have tried to find out what the function of kainate receptors is in synaptic physiology and in brain pathologies,” says the researcher.

His laboratory has made significant progress in understanding the roles of these proteins in synaptic communication, which, when dysfunctional, generates multiple neurological and neuropsychiatric disorders. This IN team had previously detected the role that the protein GluK4, one of the five subunits that form the kainate receptors, can play when overexpressed in pathologies such as autism, depression and anxiety. They also demonstrated that the protein GluK1 is found tripled in patients with Down syndrome, and that these unbalanced levels are responsible for the spatial memory deficits of these patients.

On the other hand, the laboratory led by Michisuke Yuzaki at the Department of Neurophysiology at the Keio University School of Medicine in Tokyo has studied the functioning of synapses in the cerebellum and has discovered that in this region there is an interaction between the proteins C1ql1 and Gai3 to enable synapse formation. The results of the new study show that, without the interaction of both proteins with kainate receptors, synapses do not form: “The collaboration between both laboratories has allowed us to combine our experience and knowledge to completely redefine synapse formation in the cerebellum,” highlights Yuzaki.

In this line, the experts confirmed that the presence of GluK4, which is expressed by cerebellar Purkinje neurons, is essential for the interaction that supports synaptic transmission between climbing fibers and these neurons to occur. To confirm this, the researchers used mouse models in which they genetically manipulated the expression of these proteins. The results of the experiments, which were carried out both in Lerma’s laboratory in Alicante and in Yuzaki’s laboratory in Tokyo, show that in the cerebellum synaptic plasticity, necessary for motor learning, is seriously affected when any of these kainate receptors is suppressed, both of which are necessary for the formation of synapses.

“Synaptic plasticity is the ability of our brain to form these connections and modulate them according to its needs,” explains researcher Ana Valero Paternain, co-author of the study, adding: “When this plasticity fails in the cerebellum, serious motor learning problems occur.” “In the laboratory we have found that when the number of synapses is reduced, mice are not able to learn motor behaviours,” says Wataru Kakegawa, from Keio University, co-author of the study.

Microscopy image showing synaptic buttons (green) of climbing fibers on a Purkinje cell (blue) of the cerebellum of a mouse, expressing kainate receptors. (Photo:/ IN / CSIC / UMH)

Synthetic synaptic connectors based on the structure of analogous proteins have been shown to be feasible in restoring damaged synapses in mouse models of Alzheimer’s disease and spinal cord injuries, therefore, the results raise promising avenues of study for future therapeutic applications.

The study is titled “Kainate receptors regulate synaptic integrity and plasticity by forming a complex with synaptic organizers in the cerebellum.” It has been published in the academic journal Cell Reports. (Source: CSIC)