Friday, 19th April 2019

 Molecular Neuropathology

    Molecular bases of neuronal plasticity

 


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Fco. Javier Díez Guerra
    
 

DSciStaff

 

 

DPublications

 

 

 

 

Research summary:

 

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Neuronal plasticity is the ability of nerve cells to adapt or change their functional properties under different conditions or scenarios of neural activity. These changes can be transient or persistent and constitute the basis of the cognitive function of the brain. Our research is directed towards the understanding of the cellular and molecular mechanisms that operate in neural networks to modulate synaptic efficiency. Our most important current goal is to disclose how calcium-binding proteins cooperate in the synaptic environment to regulate neuronal plasticity. Neuronal activity patterns trigger intracellular calcium oscillations that modulate a large number of signaling pathways, most of them transduced by the calcium-binding protein calmodulin (CaM). Despite its abundance, the availability of CaM against its multiple effectors is regulated by the presence of proteins such as GAP-43 and neurogranin (Ng), which sequester and accumulate CaM at pre- or post-synaptic sites, respectively. Both Ng and GAP-43 are abundant in neurons and their ability to locally accumulate CaM depends on low levels of intracellular calcium and their phosphorylation by protein kinase C. Our hypothesis is that GAP-43 and Ng act in two ways: one, by preventing activation of CaM effectors in response to subthreshold stimuli (noise suppression) and, the other, by favoring and enhancing downstream activation of some signaling pathways over others. Our ongoing research lines are now focused on the activity-dependent regulation of Ng translation in dendrites and also on the regulation of its intracellular localization. Regarding this last project we have shown that Ng translocates to the nucleus in response to synaptic activity and also that Ng specifically binds to phosphatidic acid (PA), a membrane phospholipid that has recently recognized as a signaling molecule. For such studies we use primary cultures of dissociated neurons obtained from murine cerebral cortex and hippocampus, combined with cell biology, biochemistry, molecular biology and advanced microscopy techniques. Ng deficiency is tightly linked to cognitive impairments in experimental animals. Such impairments are present in a plethora of neurological diseases, including neurodegenerative disorders, hypothyroidism or schizophrenia. We believe that Ng is an excellent target for the design and development of drugs and therapies aimed to improve our cognitive skills. A wider and deeper knowledge on CaM-sequestering proteins in the context of neuronal plasticity and its mechanisms will foster the emergence of new drugs and therapies that enhance the quality of life of aging individuals and patients suffering neurological diseases.


 

Relevant publications:

http://www.ncbi.nlm.nih.gov/pubmed/22143179

http://www.ncbi.nlm.nih.gov/pubmed/21732308

http://www.ncbi.nlm.nih.gov/pubmed/20665622

http://www.ncbi.nlm.nih.gov/pubmed/19751214

http://www.ncbi.nlm.nih.gov/pubmed/17919119

http://www.ncbi.nlm.nih.gov/pubmed/17295609

http://www.ncbi.nlm.nih.gov/pubmed/16517408

 

 

 

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