title: Selective reorganization of GABAergic transmission in neonatal ventral hippocampal-lesioned rats.
abstract: Post-mortem studies suggested a disturbance of the GABAergic system in schizophrenia. Neonatal ventral hippocampal-lesioned (NVHL) rats were used as a neurodevelopmental model of schizophrenia. Here, we characterized the GABAergic system, focusing on the GABA-synthesizing enzyme, GAD67, GABAergic interneuron characteristic proteins, and the GABA transporter, gat-1. As the GABAergic system is crucial to brain excitability, the sensitivity to pentylenetetrazol (PTZ) administration, an antagonist of GABAA receptors, was also evaluated in such rats. Male pups were lesioned with ibotenic acid at postnatal day 7. As adults, they were submitted to standard behavioural tests, i.e. prepulse inhibition of the startle reflex and increased locomotion under apomorphine, to assess the effectiveness of the lesions and the PTZ infusion test before immunohistochemistry of the GABAergic neuron markers. We found a widespread perturbation of the enzyme responsible for GABA synthesis, GAD67 and a decrease of specific interneurons, restricted to the hippocampus, entorhinal and prefrontal cortex, but no alteration of gat-1-positive fibres. The usual behavioural properties of the model, such as hyperlocomotion under apomorphine and a deficit in sensorimotor gating were confirmed. NVHL rats showed changes in cortical excitability reflected by higher susceptibility than sham-operated rats to spike wave discharges and decreased susceptibility to clonic seizures, induced by increasing the dose of PTZ. These findings indicate that a neonatal lesion of the ventral hippocampus elicits alterations in the GABAergic system leading to functional consequences on brain excitability, lending support to the idea that GABAergic systems could be involved in the pathophysiology of schizophrenia.
authors.affiliation: INSERM U666, University Louis Pasteur, Strasbourg, France. j.francois@alsace.u-strasbg.fr
authors.forename: Jennifer
authors.initials: J
authors.lastname: François
authors.forename: Arielle
authors.initials: A
authors.lastname: Ferrandon
authors.forename: Estelle
authors.initials: E
authors.lastname: Koning
authors.forename: Marie-José
authors.initials: MJ
authors.lastname: Angst
authors.forename: Guy
authors.initials: G
authors.lastname: Sandner
authors.forename: Astrid
authors.initials: A
authors.lastname: Nehlig
mesh_terms: D000161:Acoustic Stimulation / Q000009:adverse effects; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D001058:Apomorphine / Q000494:pharmacology; D064032:Calbindin 2; D064026:Calbindins; D018491:Dopamine Agonists / Q000494:pharmacology; D004569:Electroencephalography / Q000379:methods; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000293:injuries* / Q000502:physiology*; D007051:Ibotenic Acid / Q000633:toxicity; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D010320:Parvalbumins / Q000378:metabolism; D010433:Pentylenetetrazole / Q000494:pharmacology; D051381:Rats; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D064032:Calbindin 2; D064026:Calbindins; D018491:Dopamine Agonists; D018756:GABA Antagonists; D050485:GABA Plasma Membrane Transport Proteins; D010320:Parvalbumins; D064030:S100 Calcium Binding Protein G; C493415:Slc6a1 protein, rat; D007051:Ibotenic Acid; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D001058:Apomorphine; D010433:Pentylenetetrazole