Impairment of cortical GABAergic synaptic transmission in an environmental rat model of autism

• Published in: The international journal of neuropsychopharmacology 2013-07, Vol.16 (6), p.1309-1318
• Main Authors: Banerjee, Anwesha, García-Oscos, Francisco, Roychowdhury, Swagata, Galindo, Luis C., Hall, Shawn, Kilgard, Michael P., Atzori, Marco
• Format: Article
• Language: English
• Subjects: Animals; Antimanic Agents - toxicity; Autistic Disorder - etiology; Autistic Disorder - pathology; Biophysics; Disease Models, Animal; Electric Stimulation; Environment; Female; GABA Agents - pharmacology; GABAergic Neurons - physiology; In Vitro Techniques; Inhibitory Postsynaptic Potentials - drug effects; Inhibitory Postsynaptic Potentials - physiology; Male; Patch-Clamp Techniques; Pregnancy; Prenatal Exposure Delayed Effects - chemically induced; Prenatal Exposure Delayed Effects - physiopathology; Rats; Rats, Sprague-Dawley; Synaptic Transmission - drug effects; Synaptic Transmission - physiology; Temporal Lobe - drug effects; Temporal Lobe - pathology; Valproic Acid - toxicity
• ISSN: 1461-1457; 1469-5111
• DOI: 10.1017/S1461145712001216

The biological mechanisms of autism spectrum disorders (ASDs) are largely unknown in spite of extensive research. ASD is characterized by altered function of multiple brain areas including the temporal cortex and by an increased synaptic excitation:inhibition ratio. While numerous studies searched for evidence of increased excitation in ASD, fewer have investigated the possibility of reduced inhibition. We characterized the cortical γ-amino butyric acid (GABA)ergic system in the rat temporal cortex of an ASD model [offspring of mothers prenatally injected with valproic acid (VPA)], by monitoring inhibitory post-synaptic currents (IPSCs) with patch-clamp. We found that numerous features of inhibition were severely altered in VPA animals compared to controls. Among them were the frequency of miniature IPSCs, the rise time and decay time of electrically-evoked IPSCs, the slope and saturation of their input/output curves, as well as their modulation by adrenergic and muscarinic agonists and by the synaptic GABAA receptor allosteric modulator zolpidem (but not by the extra-synaptic modulator gaboxadol). Our data suggest that both pre- and post-synaptic, but not extra-synaptic, inhibitory transmission is impaired in the offspring of VPA-injected mothers. We speculate that impairment in the GABAergic system critically contributes to an increase in the ratio between synaptic excitation and inhibition, which in genetically predisposed individuals may alter cortical circuits responsible for emotional, communication and social impairments at the core of ASD.