4th International Conference on Neurology and Brain Disorders

September 09-11, 2021

September 09 -11, 2021 | Virtual Event
INBC 2021

Georgina Rodríguez de Lores Arnaiz

Speaker at Neurology and Brain Disorders 2021 - Georgina Rodríguez de Lores Arnaiz
University of Buenos Aires, Argentina
Title : Is there a relationship between the alteration of synaptic proteins of the complex PSD-95/NMDA receptor/nNOS and brain disorders?

Abstract:

Evidences point to the notion that the complex PSD-95/NMDA receptor/nNOS seems to play a key role in normal neuronal functions like synaptic plasticity, learning  and memory, as well as in brain disorders such as stroke, pain and autism. PSD-95 is one of the two most abundant postsynaptic proteins in the postsynaptic density (PSD) which plays a pivotal role in the coupling between NMDA receptors and nNOS and can modulate the synaptic expression of glutamate receptors by binding to GluN2A and GluN2B, thereby stabilizing NMDA receptors at the cell surface. Uncoupling nNOS from the NMDA-receptor through the scaffolding protein PSD-95 produces behavioral antidepressant effects resembling the effects of NOS inhibitors and exerts a neuroprotective action against stroke. Given that ATP provision by mitochondria may play an important role in the functional interaction between synaptic proteins NMDA receptor and PSD-95 with NO synthesis, we became interested in the study of synaptic proteins of the complex PSD-95/NMDA receptor/nNOS and mitochondrial functionality. The study was conducted in fractions isolated from rat cerebral cortex after administration of levocabastine, a drug employed as a tool to block the low affinity neurotensin receptors. Male Wistar rats received a single (i.p.) dose of levocabastine (50 μg/kg) or saline solution (controls) and were decapitated 18 hours later. Synaptosomal membranes were obtained and expression of synaptic proteins was evaluated by Western blot assays. After levocabastine treatment, protein expression of PSD-95, nNOS and GluN2B subunit of NMDA receptor decreased 97%, 56% and 45%, respectively versus controls. At variance, expression of iNOS enhanced 3.5-fold versus controls. In crude mitochondrial fractions, levocabastine administration reduced roughly 15% respiratory control rate as assayed with malate-glutamate or succinate as substrates, decreased mitochondrial membrane potential (21%), and ATP production rates (57%).

In addition, a 55% decrease in beta actin was observed. Alterations in actin cytoskeleton might then be a consequence of ATP deficit but may also lead to impairment of mitochondrial dynamics, which in turn would result in further mitochondrial dysfunction and ATP depletion.

Results indicated that levocabastine administration induces alterations in synaptic proteins of the complex PSD-95/NMDA receptor/nNOS and in neuron cytoskeleton. Mitochondrial bioenergetics impairment may play a role in the functional link between synaptic proteins and NO synthesis.

In addition, levocabastine can impair mitochondrial function in in vitro conditions. This direct effect of levocabastine on mitochondrial bioenergetics might lead to alteration of the integrity of functional complex PSD-95/NMDA receptor/nNOS, due to the decrease in ATP formation which is required for protein assembly. To sum up, present results showed important changes in specific synaptic proteins and mitochondria functionality, suggesting an impairment of PSD-95/NMDA receptor/nNOS complex integrity. At synaptic sites, mitochondrial dysfunction might influence the interaction between these proteins inter se, and with other specialized molecules involved in neurotransmitter processes as well as in signaling processes. Further studies may help to understand the role of synaptic complex PSD-95/NMDA receptor/nNOS in brain disorders at cellular and molecular levels and might contribute to the future development of pharmacological treatment options.

Biography:

Dr.Georgina Rodríguez de Lores Arnaiz is a Farmacist (1957), Biochemist (1959), Doctor in Pharmacy and Biochemistry (1961). Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires. 

Present Position:

  • CONICET Superior Investigator at Instituto de Biología Celular y Neurociencias “Prof. E. De Robertis” (IBCN) CONICET-UBA, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155-1121-Buenos Aires. Argentina. 
  • Editor for Research Topic “Neurochemistry – Neuropharmacology”, Frontiers in Pharmacology.
  • Emeritus Member at International Society for Neurochemistry, American Society for Neurochemistry, Society for Neuroscience.
  • Steering Committee and Editorial Board Member at Sociedad Científica Argentina (SCA).

Previous positions

  • Pharmacology, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires  
  • Editorial Board Member for Neurochemical Research (1989-1999) and Journal of Neurochemistry and Book Editor on Function of neuropeptides at central nervous system (2009). She published more than 150 research articles in international scientific journals.

 

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