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Synaptic Physiology

Principal investigator: Juan Lerma , Ph.D.

Group research focus

Glutamate acts as a neurotransmitter at most excitatory synapses and is involved in long-lasting plastic phenomena as well as in neuronal dead-associated pathology such as neurodegeneration. During previous projects, our group have characterized and identified functions for one of the glutamate receptors largely elusive to researchers, the kainate receptor (KAR). Two fundamental findings paved the way to this extent. Once the existence of these receptors in central neurons was demonstrated, the identification of a selective antagonist made possible their pharmacological isolation. As a result, we and others have found that the function of KARs is double.

They may work presynaptically to modulate transmitter release and postsynaptically, mediating part of the synaptic transmission at certain central synapses. Therefore, we have concentrated in getting insights into the knowledge of these two functions in the brain. Moreover, although these receptors are ion channels, some of their modulatory capabilities involve triggering of a cascade of second messengers, implicating the existence of a non-canonical signalling pathway. We have identified the elements (or part of them) involved in such a pathway as well as identified some of their functional roles in several aspects of the brain physiology.

Objectives

The understanding of brain diseases requires the definition of the molecular, synaptic and cellular alterations underpinning the behavioral features that define the disease. It now seems that KARs may have a role in syndromes such as schizophrenia, bipolar disorders and autism that is to be delineated. The role played by KARs in brain physiology is much more poorly understood than that of other glutamate receptors, yet it is now clear that they play significant roles in synapses and in the maturation of neural circuits during development. Alteration of glutamatergic neurotransmission is considered a major contributing factor of mental disorders and neurodegenerative diseases and some experimental data implicate KARs on certain affective disorders. Recent results from our lab indicate that animals overexpressing high affinity subunits of KARs show more efficient information transfer through the hippocampal trisynaptic circuit, at the same time displaying anhedonia, enhanced anxiety and depressive states, as well as impaired social interaction, common endophenotypes associated to autism.

These data may be relevant to humans since a child with autism has been found to have duplicated a chromosomal segment encompassing GRIK4, the gen coding for GluK4, likely identifying a role for excess of function of KARs in human disease. These new and exciting data lead us to approach the general objective of getting insights into the role played by KARs in the pathophysiology of brain diseases, namely those related to the alteration of the mood. We are currently generating mouse models to try to understand the relationship between brain circuits and behavior. To this end we use functional (in vivo and in vitro electrophysiological, Ca2+ imaging…), morphological (immunocytochemistry, quantitative imaging…) and behavioral approaches. All with the aim of contributing to one of the main challenges in neuroscience research, bridge the gap between cellular and molecular properties of brain processes and behavior.

scheme-synaptic-physiology

Ongoing collaborative research

Recent publications