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Neurobiology of ionotropic Glutamate receptors in health and disease

Principal investigator: Xavier Altafaj , Ph.D.

Group research focus

The iGluRsNeuroLab aims to understand the physiology of NMDA-type ionotropic glutamate receptors (iGluRs) and to unveil the molecular and cellular mechanisms bridging the gap between glutamate receptor dysfunctions and neurological diseases, towards the development of targeted therapeutic approaches. Our efforts are focused to elucidate the molecular mechanisms underlying synaptic plasticity processes in post-synaptic glutamatergic neurons. In particular, we aim to understand the post-translational mechanisms (mainly focusing on phosphorylation events) that regulate iGluRs trafficking and behaviour under physiological conditions and their alterations in neurological disorders. The molecular insights are finally used to design targeted therapeutic approaches and to evaluate their efficacy to attenuate iGluR-mediated neuronal dysfunctions.

The surface expression of NMDARs is a critical regulatory mechanism of NMDA-mediated glutamatergic transmission.

The surface expression of NMDARs is a critical regulatory mechanism of NMDA-mediated glutamatergic transmission.

Methodologically, our experimental strategy starts with the identification of genetic and biochemical alterations of iGluRs in different pathological conditions, both from patients and from animal models. We then evaluate in vitro, the impact of these alterations using cellular models (mouse primary cortical and hippocampal neurons, cell lines). In these models, we study the trafficking of iGluRs towards the plasma membrane, their internalization rate, protein-protein interactions and, in collaboration with electrophysiologists, the potential biophysical changes of altered iGluRs. Further, these findings are translated to mouse models, both to evaluate the physiological relevance of in vitro findings and to develop results-driven therapeutic approaches, along the phenotypic assessment of treated mouse models.

Objectives

Transient expression of GluN2B subunit of NMDAR, carrying a de novo mutation associated with intellectual disability.

Transient expression of GluN2B subunit of NMDAR, carrying a de novo mutation associated with intellectual disability.

Along these years, we have investigated the possibility to attenuate both motor and cognitive alterations in adult murine models of Down syndrome (DS), through the normalization of the expression levels of DYRK1A kinase, a DS candidate gene, using a gene therapy approach. These proof-of-concept studies allow to envision the exciting possiblity to treat intellectual disability (ID) in the adulthood, by the intervention of defined gene targets. The molecular insights obtained during this project also shown the relationship between DYRK1A and the ionotropic NMDA-type of glutamate receptors. My laboratory invested most of the efforts to elucidate the relationship between this kinase and NMDARs, and we identified DYRK1A as a novel kinase phosphorylating NMDARs and regulating their trafficking as well as their activity.

In vivo manipulation of murine models with intellectual disability.

In vivo manipulation of murine models with intellectual disability.

Taken together our theoretical and technical expertise in the study of NMDARs and ID conditions, our ongoing and future research projects are focused to understand the role of NMDARs dysfunctions in different neurological conditions associated to cognitive dysfunction (Down syndrome, Non-syndromic intellectual disability, Alzheimer’s disease). In particular, we are interested to understand the effect of NMDARs de novo mutations in patients with intellectual disability, and to study the effect of the subcellular distribution of NMDARs in Alzheimer’s disease progression. These projects will contribute, in a medium- and long-term, to understand the contribution of NMDARs dysregulation to synaptic dysfunction and to the associated cognitive impairment. Ultimately, these achievements will be used to design and develop therapeutic strategies towards the attenuation, delay or blockade of the synaptic alterations leading to cognitive impairment. More precisely, the specific ongoing projects developed in our group, in collaboration with other groups of the SynCogDys network, are:

  1. Study of NMDA receptor trafficking and channel activity regulation by phosphorylation.
  2. Study of the functional impact of iGluRs de novo mutations in patients with intellectual disability.
  3. Study of NMDA receptor macromolecular complexes in the early stages of Alzheimer’s disease.
  4. Characterization of glutamatergic system alterations in Down syndrome murine models and development of gene therapy strategies.

Ongoing collaborative research

Publications in collaboration with network members

Recent publications