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Cellular Biology of the Synapse

Principal investigator: Isabel Pérez Otaño , Ph.D.

Group research focus

Development and refinement of neural circuits

Efficient delivery of short-hairpins RNAs towards GluN3A into adult mouse striatum using estereotaxic injection

Efficient delivery of short-hairpins RNAs towards GluN3A into adult mouse striatum using estereotaxic injection

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. Critical periods are important medically because some types of experience-dependent wiring no longer occur after they end, or when the proteins and genes supporting this wiring work incorrectly.

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Medium spiny neuron grown in primary culture carries a large mutant huntingtin aggregate (yellow).

Research in my lab is interested in two main questions. 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? Over the past few years, we have focused on the biological roles of a novel class of NMDA-type glutamate receptors that contain GluN3A subunits. GluN3A-NMDARs are highly expressed during postnatal critical periods and play critical roles in preventing premature or disordered synapse stabilization and maturation and in targeting non-used synapses for pruning (Roberts et al, Neuron 2009, Fiuza et al, PNAS 2013, Kehoe et al, J Neuroscience 2014). Later on, GluN3A expression is largely down-regulated by trafficking mechanisms that we have started to identify and that permit the removal of GluN3A and associated maturation of only subsets of synapses (Pérez-Otaño, Nature Neuroscience 2006, Chowdhury et al, J Neuroscience 2013). 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 (Marco et al, Nature Medicine 2013, Yuan et al Neuron 2013).

Current projects

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Visualization of neuronal morphology upon transfection of cultured hippocampal neurons with green fluorescent protein. Enhancing GluN3A levels over the period of synaptic refinement causes synapse loss. Synapse loss requires binding to the postsynaptic scaffold GIT1 (Fiuza et al, PNAS 2013).

  1. Mechanisms for selective synapse selection: The goal is to define the mechanisms that mediate GluN3A-induced synapse pruning and to test their impact on synaptic connectivity, cognition and disease.
  2. Cell biology of GluN3A down-regulation: Because of the key role of GluN3A down-regulation in the emergence of mature neural circuits, we continue to be interested in the mechanisms that turn-off expression and their dependence on activity. We are developing genetic and imaging tools to activate GluN3A-selective endocytosis pathways in a synapse-specific manner and test whether they provide a mechanism for maturation of only active synapses.
  3. Discovery and targeting of disease mechanisms: Alterations in excitatory neurotransmission are major factors in the pathophysiology of neurodegenerative and neuropsychiatric diseases. One source of these alterations is a failure to maintain the balance between synapse maturation and pruning, 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.

Ongoing collaborative research

Recent publications