Subchronic phencyclidine treatment in adult mice increases GABAergic transmission and LTP threshold in the hippocampus.
Repeated administration of non-competitive N-methyl-d-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) to rodents causes long-lasting deficits in cognition and memory, and has effects on behaviors that have been suggested to be models of the cognitive impairment associated with schizophrenia (CIAS). Despite this being a widely studied animal model, little is known about the long lasting changes in synapses and circuits that underlie the altered behaviors. Here we examined synaptic transmission ex-vivo in the hippocampus of mice after a subchronic PCP (scPCP) administration regime. We found that after at least one week of drug free washout period when mice have impaired cognitive function, the threshold for long-term potentiation (LTP) of CA1 excitatory synapses was elevated. This elevated LTP threshold was directly related to increased inhibitory input to CA1 pyramidal cells through increased activity of GABAergic neurons. These results suggest repeated PCP administration causes a long-lasting metaplastic change in the inhibitory circuits in the hippocampus that results in impaired LTP, and could contribute to the deficits in hippocampal-dependent memory in PCP-treated mice. Changes in GABA signaling have been described in patients with schizophrenia, therefore our results support using scPCP as a model of CIAS. This article is part of the Special Issue entitled 'Synaptopathy--from Biology to Therapy'.
Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Toshihiro
T
Nomura
Department of Psychiatry, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
Yoshihiro
Y
Oyamada
Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Herman B
HB
Fernandes
Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Christine L
CL
Remmers
Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Jian
J
Xu
Department of Psychiatry, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Herbert Y
HY
Meltzer
Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Department of Neurobiology, Weinberg College of Arts and Sciences, Northwestern University, Chicago, IL 60611, USA. Electronic address: a-contractor@northwestern.edu.
Anis
A
Contractor
D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects* / Q000502:physiology; D017774:Long-Term Potentiation / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D010622:Phencyclidine / Q000008:administration & dosage*; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D055366:Synaptic Potentials / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D005680:gamma-Aminobutyric Acid; D010622:Phencyclidine
GABA; Hippocampus; Inhibitory postsynaptic current; Long-term potentiation; Phencyclidine