title: Alterations in hippocampal excitability, synaptic transmission and synaptic plasticity in a neurodevelopmental model of schizophrenia.
abstract: The risk of developing schizophrenia has been linked to perturbations in embryonic development, but the physiological alterations that result from such insults are incompletely understood. Here, we have investigated aspects of hippocampal physiology in a proposed neurodevelopmental model of schizophrenia, induced during gestation in rats by injection of the antimitotic agent methylazoxymethanol acetate (MAM) at embryonic day 17 (MAM(E17)). We observed a reduction in synaptic innervation and synaptic transmission in the dorsal hippocampus of MAM(E17) treated rats, accompanied by a pronounced increase in CA1 pyramidal neuron excitability. Pharmacological investigations suggested that a deficit in GABAergic inhibition could account for the increase in excitability; furthermore, some aspects of the hyper-excitability could be normalised by the GABA(A) receptor (GABA(A)R) potentiator diazepam. Despite these alterations, two major forms of synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD) could be readily induced. In contrast, there was a substantial deficit in the reversal of LTP, depotentiation. These findings suggest that delivering neurodevelopmental insults at E17 may offer insights into some of the physiological alterations that underlie behavioural and cognitive symptoms observed in schizophrenia.
authors.affiliation: Centre for Cognitive Neuroscience, Eli Lilly and Co., Erl Wood Manor, Windlesham GU20 6PH, UK. thomassanderson@snu.ac.kr
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Sanderson
authors.forename: Marie-Caroline
authors.initials: MC
authors.lastname: Cotel
authors.forename: Michael J
authors.initials: MJ
authors.lastname: O'Neill
authors.forename: Mark D
authors.initials: MD
authors.lastname: Tricklebank
authors.forename: Graham L
authors.initials: GL
authors.lastname: Collingridge
authors.forename: Emanuele
authors.initials: E
authors.lastname: Sher
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism*; D008297:Male; D008746:Methylazoxymethanol Acetate / Q000633:toxicity; D009473:Neuronal Plasticity / Q000187:drug effects; D009924:Organ Culture Techniques; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000139:chemically induced / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D008746:Methylazoxymethanol Acetate