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Research Group
Development and refinement of neural circuits
Unit Unit Cellular and Systems Neurobiology »

Principal Investigator Ph.D. Investigator Graduate students / Research Assistant Master Students Technician
Research Fields
A fundamental question in neuroscience is how neuronal circuits are refined by environmental cues. Circuit refinements involve maturation of selected synaptic connections and elimination (“pruning”) of others and are most prominent during critical periods—a stage of postnatal brain development when synapses have a high potential for undergoing plasticity. This malleability allows early experience to modify the architecture of neural circuits, providing a foundation for future learning. Perhaps more importantly, it shapes (often permanently) the cognitive, social and emotional abilities of an individual so it can adapt to the environment at hand. Critical periods are of medical relevance as well because some types of experience-dependent wiring no longer occur after they end, or when the proteins and genes supporting this wiring work incorrectly.

Our work focuses on two major aspects. First, what are the basic mechanisms that control the development, refinement, and homeostasis of neural circuits? Second, what goes wrong in disorders of brain development, cognition or memory?

In the past 10 years, we have defined the biological functions of a new class of NMDA-type glutamate receptors that contain GluN3A subunits and are typically expressed during the critical period in many brain regions and cell types. They have crucial roles in preventing premature or disordered synapse stabilization and maturation and in targeting non-used synapses for pruning. Later, GluN3A-containing NMDA receptor expression is largely down-regulated via a combination of mechanisms. Prolonging or switching back GluN3A expression in adult brains reactivates a juvenile state of enhanced pruning and underlies circuit rearrangements that underlie the pathophysiology of Huntington’s disease (HD) and cocaine addiction.

Current projects investigate:
1. Cell biology mechanisms underlying synapse pruning
2. Impact of early synaptic remodeling on the emergence of cognitive and emotional capabilities
3. Discovery and targeting of disease mechanisms: Failure to maintain the balance between synapse maturation and pruning is at the root of neurodegenerative and neuropsychiatric disorders, leading to impaired connectivity and circuit dysfunctions. We have shown that adult reactivation of GluN3A expression is at the basis of Huntington´s disease and are currently exploring its involvement in alcohol abuse and other forms of addiction. Work in the lab is also directed to develop pharmacological/gene therapies to block GluN3A function or expression, and test whether they promote recovery of function.

Representative Publications

Murillo, A. , Navarro, A.I., Puelles, E., Zhang, Y., Petros, T., Pérez-Otaño, I " Temporal dynamics and neuronal specificity of Grin3a expression in the mouse forebrain. " Cerebral Cortex . doi.org , /10.1093/cercor/bhaa330 - ( 2020 )

Pérez-Otaño I. , Larsen RS, Wesseling JF. " Emerging roles of non-conventional NMDA receptors in synapse development and disease. " Nature Reviews in Neuroscience . 17(10) , 623 - 35 ( 2016 )

Fiuza M. , González-González I, Pérez-Otaño I. " GluN3A expression restricts maturation of inactive synapses via direct binding to GIT1. " Proc Natl Acad Sci USA . 110(51) , 20807 - 12 ( 2013 )

Marco S. , Giralt, A., Petrovic M., Pouladi, M., Torres-Peraza, J., Watanabe, M., Graham, R.K., Hayden, M.R., Wesseling, J.F., Alberch, J., Pérez-Otaño, I. " Suppressing aberrant GluN3A expression rescues synaptic and behavioral impairments in Huntington's disease models. " Nature Medicine . 19 , 1030 - 1038 ( 2013 )

Roberts, A. , Díez-García, J., Rodriguiz, R., López-García, I., Martínez-Turrillas, R., Picó, E., Luján, R., Henson, M.E., López-Mascaraque, L., Feng, G., Lo, D.C., Wesseling, J.F., Wetsel, W.C., Philpot, B.D., Pérez-Otaño, I. " Developmental down-regulation of NR3A-containing NMDA receptors is required for synapse maturation and memory consolidation. " Neuron . 63 , 342 - 356 ( 2009 )
Consejo Superior de Investigaciones Científicas
Universidad Miguel Hernández

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