Neurobiology of Fetal Alcohol Spectrum Disorder: Ethanol has unique effects on synaptic transmission and plasticity in the developing nervous system.  Dr. Valenzuela first showed that the effect of ethanol on immature GABAergic neurons is actually excitatory (Galindo et al., 2005), suggesting that the hyperexcitability from repeated intermittent exposure to ethanol during this period of brain development may underlie a long-lasting diminished responsiveness of hippocampal circuitry to excitatory neurotransmission.  His laboratory also demonstrated that: 1) AMPA receptors (instead of NMDA receptors) and N-type voltage-gated Ca²⁺ channels are very sensitive targets of ethanol during the 3rd trimester-equivalent (Mameli et al., 2005); 2) ethanol exposure during the 3rd trimester-equivalent inhibits long-term potentiation in the CA1 hippocampal region (Puglia et al., 2010a,b), and 3) that ethanol exposure during the 3rd trimester-equivalent inhibits BDNF-dependent GABAergic plasticity in hippocampal neurons (Zucca et al., 2010).  Moreover, his laboratory rigorously tested the “excessive inhibition” hypothesis of FASD, providing evidence inconsistent with this model (Sanderson et al., 2009).

Modulation of Cerebellar Circuits by Alcohol:  The cerebellum is involved in the control of balance as well as the coordination, planning and fine regulation of voluntary movement. It is now widely recognized that the cerebellum also plays a role in higher-order cognitive and emotional functions and that cerebellar alterations may be involved in the pathophysiology of several neuropsychiatric disorders including alcoholism.  Executive function abnormalities in alcoholics are in part a consequence of frontocerebellar circuitry dysfunction.  Short and long-term exposure to ethanol causes cerebellar impairment and this is responsible for a large number of accidental injuries/deaths worldwide. Fetal alcohol spectrum disorder is characterized by cerebellar neuronal loss and synaptic transmission/plasticity alterations.  Despite the importance of the cerebellum as a target of ethanol, little is known about its mechanism of action in this brain region.  During the past 10 years, we discovered many novel actions of ethanol at cerebellar synapses.  First, we reported that ethanol increases inhibitory neurotransmission mediated by extrasynaptic GABA-A receptors at cerebellar granule neurons.  Second, we showed that this effect is mediated via an indirect mechanism that involves an increase in GABA release from a specialized GABAergic neuron (i.e. the Golgi cell) which innervates the granule cell.  Third, we demonstrated that ethanol excites the Golgi cell by inhibiting the Na⁺/K⁺ ATPase and a quinidine-sensitive potassium channel.   Fourth, we found that ethanol increases inhibitory input to Purkinje neurons, which constitute the sole output of the cerebellar cortex.  Fifth, we showed that ethanol affects synaptic plasticity at excitatory synapses in Purkinje neurons.  Findings of these studies will lay 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