title: Synaptic transmission changes in fear memory circuits underlie key features of an animal model of schizophrenia.
abstract: Non-competitive antagonists of the N-methyl-d-aspartate receptor (NMDA) such as phencyclidine (PCP) elicit schizophrenia-like symptoms in healthy individuals. Similarly, PCP dosing in rats produces typical behavioral phenotypes that mimic human schizophrenia symptoms. Although schizophrenic behavioral phenotypes of the PCP model have been extensively studied, the underlying alterations of intrinsic neuronal properties and synaptic transmission in relevant limbic brain microcircuits remain elusive. Acute brain slice electrophysiology and immunostaining of inhibitory neurons were used to identify neuronal circuit alterations of the amygdala and hippocampus associated with changes in extinction of fear learning in rats following PCP treatment. Subchronic PCP application led to impaired long-term potentiation (LTP) and marked increases in the ratio of NMDA to 2-amino-3(5-methyl-3-oxo-1,2-oxazol-4-yl)propionic acid (AMPA) receptor-mediated currents at lateral amygdala (LA) principal neurons without alterations in parvalbumin (PV) as well as non-PV, glutamic acid decarboxylase 67 (GAD 67) immunopositive neurons. In addition, LTP was impaired at the Schaffer collateral to CA1 hippocampal pathway coincident with a reduction in colocalized PV and GAD67 immunopositive neurons in the CA3 hippocampal area. These effects occurred without changes in spontaneous events or intrinsic membrane properties of principal cells in the LA. The impairment of LTP at both amygdalar and hippocampal microcircuits, which play a key role in processing relevant survival information such as fear and extinction memory concurred with a disruption of extinction learning of fear conditioned responses. Our results show that subchronic PCP administration in rats impairs synaptic functioning in the amygdala and hippocampus as well as processing of fear-related memories.
authors.affiliation: Janssen Research & Development, A division of Janssen Pharmaceutica NV, Beerse, Belgium. mpollard1@its.jnj.com
authors.forename: Marie
authors.initials: M
authors.lastname: Pollard
authors.forename: Christophe
authors.initials: C
authors.lastname: Varin
authors.forename: Brian
authors.initials: B
authors.lastname: Hrupka
authors.forename: Darrel J
authors.initials: DJ
authors.lastname: Pemberton
authors.forename: Thomas
authors.initials: T
authors.lastname: Steckler
authors.forename: Hamdy
authors.initials: H
authors.lastname: Shaban
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000679:Amygdala / Q000473:pathology; D000818:Animals; D019540:Area Under Curve; D001703:Biophysics; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005108:Extinction, Psychological / Q000187:drug effects; D005239:Fear; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D008569:Memory Disorders / Q000209:etiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010320:Parvalbumins / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010622:Phencyclidine / Q000633:toxicity; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000139:chemically induced / Q000150:complications* / Q000473:pathology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
chemical_list: D018691:Excitatory Amino Acid Antagonists; D010320:Parvalbumins; D011810:Quinoxalines; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D010622:Phencyclidine