title: Hippocampal hyperexcitability in fetal alcohol spectrum disorder: Pathological sharp waves and excitatory/inhibitory synaptic imbalance.
abstract: Prenatal alcohol exposure (PAE) can lead to long-lasting neurological alterations that may predispose individuals to seizures and neurobehavioral dysfunction. To date, there exists limited information regarding the underlying pathophysiological mechanisms. The hippocampal CA3 region generates excitatory population activity, called sharp waves (SPWs), that provide an ideal model to study perturbations in neuronal excitability at the network and cellular levels. In the present study, we utilized a mouse model of PAE and used dual extracellular and whole-cell patch-clamp recordings from CA3 hippocampal pyramidal cells to evaluate the effect of 1st trimester-equivalent ethanol exposure (10% v/v) on SPW activity and excitatory/inhibitory balance. We observed that PAE significantly altered in vitro SPW waveforms, with an increased duration and amplitude, when compared to controls. In addition, PAE slices exhibited reduced pharmacological inhibition by the GABA-A receptor antagonist bicuculline (BMI) on SPW activity, and increased population spike paired-pulse ratios, all indicative of network disinhibition within the PAE hippocampus. Evaluation of PAE CA3 pyramidal cell activity associated with SPWs, revealed increased action potential cell firing, which was accompanied by an imbalance of excitatory/inhibitory synaptic drive, shifted in favor of excitation. Moreover, we observed intrinsic changes in CA3 pyramidal activity in PAE animals, including increased burst firing and instantaneous firing rate. This is the first study to provide evidence for hippocampal dysfunction in the ability to maintain network homeostasis and underlying cellular hyperexcitability in a model of PAE. These circuit and cellular level alterations may contribute to the increased propensity for seizures and neurobehavioral dysfunction observed in patients with a history of PAE.
authors.affiliation: Division of Fundamental Neurobiology, Toronto Western Research Institute, UHN, Toronto, ON, Canada. Electronic address: michal.krawczyk@ucalgary.ca.
authors.forename: Michal
authors.initials: M
authors.lastname: Krawczyk
authors.affiliation: Division of Fundamental Neurobiology, Toronto Western Research Institute, UHN, Toronto, ON, Canada.
authors.forename: Meera
authors.initials: M
authors.lastname: Ramani
authors.affiliation: Division of Fundamental Neurobiology, Toronto Western Research Institute, UHN, Toronto, ON, Canada.
authors.forename: Josh
authors.initials: J
authors.lastname: Dian
authors.affiliation: Division of Fundamental Neurobiology, Toronto Western Research Institute, UHN, Toronto, ON, Canada.
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Florez
authors.affiliation: Division of Fundamental Neurobiology, Toronto Western Research Institute, UHN, Toronto, ON, Canada.
authors.forename: Shanthini
authors.initials: S
authors.lastname: Mylvaganam
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.
authors.forename: James
authors.initials: J
authors.lastname: Brien
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.
authors.forename: James
authors.initials: J
authors.lastname: Reynolds
authors.affiliation: Division of Clinical Pharmacology & Toxicology, The Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Bhushan
authors.initials: B
authors.lastname: Kapur
authors.affiliation: Department of Biology, York University, Toronto, ON, Canada; Department of Psychology, York University, Toronto, ON, Canada.
authors.forename: Georg
authors.initials: G
authors.lastname: Zoidl
authors.affiliation: Robarts Research Institute and Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada.
authors.forename: Michael O
authors.initials: MO
authors.lastname: Poulter
authors.affiliation: Division of Fundamental Neurobiology, Toronto Western Research Institute, UHN, Toronto, ON, Canada; Department of Medicine (Neurology), University of Toronto, Toronto, ON, Canada; Department of Physiology, University of Toronto, Toronto, ON, Canada.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Carlen
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D056654:CA3 Region, Hippocampal / Q000473:pathology* / Q000503:physiopathology*; D004195:Disease Models, Animal; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000473:pathology*; D018682:GABA Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000502:physiology*; D018709:Statistics, Nonparametric; D055366:Synaptic Potentials / Q000187:drug effects / Q000502:physiology*
chemical_list: D018683:Excitatory Amino Acid Agents; D018682:GABA Agents
keywords: Electrophysiology; Fetal alcohol spectrum disorder; Hippocampus; Hyperexcitability; Prenatal alcohol exposure; Sharp waves