Hippocampal hyperexcitability in fetal alcohol spectrum disorder: Pathological sharp waves and excitatory/inhibitory synaptic imbalance

Michal Krawczyk; Meera Ramani; Josh Dian; Carlos M Florez; Shanthini Mylvaganam; James Brien; James Reynolds; Bhushan Kapur; Georg Zoidl; Michael O Poulter; Peter L Carlen

doi:10.1016/j.expneurol.2016.03.013

Hippocampal hyperexcitability in fetal alcohol spectrum disorder: Pathological sharp waves and excitatory/inhibitory synaptic imbalance

Exp Neurol. 2016 Jun:280:70-9. doi: 10.1016/j.expneurol.2016.03.013. Epub 2016 Mar 18.

Authors

Affiliations

¹ Division of Fundamental Neurobiology, Toronto Western Research Institute, UHN, Toronto, ON, Canada. Electronic address: michal.krawczyk@ucalgary.ca.
² Division of Fundamental Neurobiology, Toronto Western Research Institute, UHN, Toronto, ON, Canada.
³ Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.
⁴ Division of Clinical Pharmacology & Toxicology, The Hospital for Sick Children, Toronto, ON, Canada.
⁵ Department of Biology, York University, Toronto, ON, Canada; Department of Psychology, York University, Toronto, ON, Canada.
⁶ Robarts Research Institute and Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada.
⁷ 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.

PMID: 26996134
DOI: 10.1016/j.expneurol.2016.03.013

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.

Keywords: Electrophysiology; Fetal alcohol spectrum disorder; Hippocampus; Hyperexcitability; Prenatal alcohol exposure; Sharp waves.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Action Potentials / drug effects
Action Potentials / physiology
Animals
Animals, Newborn
CA3 Region, Hippocampal / pathology*
CA3 Region, Hippocampal / physiopathology*
Disease Models, Animal
Excitatory Amino Acid Agents / pharmacology
Female
Fetal Alcohol Spectrum Disorders / pathology*
GABA Agents / pharmacology
In Vitro Techniques
Male
Mice
Mice, Inbred C57BL
Patch-Clamp Techniques
Pyramidal Cells / physiology*
Statistics, Nonparametric
Synaptic Potentials / drug effects
Synaptic Potentials / physiology*

Substances

Excitatory Amino Acid Agents
GABA Agents

Grants and funding

ELA-80227/CIHR/Canada