C. Fernando Valenzuela, M.D., Ph.D.
M.D., Colombian School of Medicine (Universidad El Bosque) Bogota, Colombia
Ph.D. in Biomedical Sciences, University of California, Riverside, CA.
Research in my laboratory focuses on modulation of developing and mature neuronal circuits by alcohol (ethanol), with the long-term goal of contributing to a better understanding of the neurobiology of alcoholism and fetal alcohol spectrum disorders (FASDs). Our main research accomplishments can be summarized as follows: 1) Novel actions of ethanol on glutamatergic transmission and plasticity. Our laboratory demonstrated that the kainate subtype of glutamate receptors is one of the most sensitive targets of ethanol in the brain (Carta et al, PNAS 2003). We showed that ethanol potently decreases the excitatory drive mediated by these receptors in GABAergic neurons of the hippocampus, an effect that can explain the paradoxical excitatory actions of low doses of ethanol. We also demonstrated that ethanol impairs a form of cerebellar synaptic plasticity that is involved in motor learning (i.e., long-term depression) and that this effect is mediated by inhibition of type-1 metabotropic glutamate receptors (Carta et al, J Neurosci 2006; Belmeguenai et al, J. Neurophysiol, 2008). This action of ethanol likely contributes to the motor incoordination, and perhaps also the cognitive impairment, associated with alcohol consumption. 2) Alcohol increases GABAergic transmission at the presynaptic level, indirectly affecting extrasynaptic GABAA receptors. We were the first to report that ethanol increases tonic inhibitory neurotransmission mediated by extrasynaptic GABAA receptors at cerebellar granule neurons and this is mediated via an increase in GABA release from Golgi interneurons. This discovery has had a significant impact in the field (Carta et al., 2004), contributing to kindle many studies in several laboratories that have demonstrated similar effects in other brain regions. It is now widely accepted that tonic inhibitory currents mediated by extrasynaptic receptors are important targets of ethanol that likely contribute to its behavioral effects, including acute intoxication, alcohol withdrawal, and addiction. Work from our laboratory has also provided additional evidence indicating that a major site of action of ethanol is at the presynaptic level, rather than the postsynaptic level as previously thought. Together with our work on cerebellar granule cells, our studies on the effect of ethanol on GABAergic transmission at Purkinje neurons clearly demonstrated that ethanol acts by increasing GABA release rather than directly potentiating GABAA receptors (Botta et al, JPET 2005). Findings of these studies have laid a solid foundation toward a better understanding of the long-term effects of ethanol in developing and mature cerebellar circuits and may also facilitate the discovery of new treatment options against alcoholism and the neurological sequelae that are associated with this disease. 3) Neurosteroids are novel modulators of developing neuronal circuits that are involved in the pathophysiology of FASDs. Our laboratory was the first to demonstrate that a pregnenolone sulfate-like neurosteroid acts as an activity-dependent retrograde messenger that increases glutamate release during a restricted developmental period. These findings represented an important paradigm shift in the field because they indicated that neurosteroids can act as retrograde messengers, similarly to other lipids such as arachidonic acid and cannabinoids (Meyer et al., JBC 2002, Mameli et al., J. Neuroscience, 2005). Importantly, we also demonstrated that fetal alcohol exposure alters sensitivity of NMDA receptors to pregnenolone sulfate-like neurosteroids, produces a dramatic elevation in the levels of these neurosteroids, and also induces premature activation of immature synapses in a neurosteroid-dependent manner.About Me
Dr. Valenzuela completed his M.D. with honors at the Universidad El Bosque (Bogota, Colombia). While in medical school, he particularly enjoyed the basic medical sciences, learning about membrane receptors, signal transduction pathways, as well as the cellular and molecular mechanisms of action of pharmacological agents. He then came to the University of California at Riverside to pursue a Ph.D. in Biomedical Sciences in the laboratory of Dr. David Johnson. His Ph.D. dissertation focused on the structure, function, and pharmacological modulation of nicotinic acetylcholine receptors. Dr. Valenzuela then pursued postdoctoral training in the laboratory of Dr. Adron Harris in Department of Pharmacology and Alcohol Research Center at the University of Colorado Health Sciences Center. At the U. of Colorado, he developed a strong interest in alcohol neurobiology research, particularly on the modulation of ion channels and synaptic transmission by ethanol. He then joined the UNM School of Medicine as a faculty member, where he began collaborative projects on the effects of ethanol on developing neuronal circuits.