title: Phencyclidine-induced loss of asymmetric spine synapses in rodent prefrontal cortex is reversed by acute and chronic treatment with olanzapine.
abstract: Enduring cognitive deficits exist in schizophrenic patients, long-term abusers of phencyclidine (PCP), as well as in animal PCP models of schizophrenia. It has been suggested that cognitive performance and memory processes are coupled with remodeling of pyramidal dendritic spine synapses in prefrontal cortex (PFC), and that reduced spine density and number of spine synapses in the medial PFC of PCP-treated rats may potentially underlie, at least partially, the cognitive dysfunction previously observed in this animal model. The present data show that the decrease in number of asymmetric (excitatory) spine synapses in layer II/III of PFC, previously noted at 1-week post PCP treatment also occurs, to a lesser degree, in layer V. The decrease in the number of spine synapses in layer II/III was sustained and persisted for at least 4 weeks, paralleling the observed cognitive deficits. Both acute and chronic treatment with the atypical antipsychotic drug, olanzapine, starting at 1 week after PCP treatment at doses that restore cognitive function, reversed the asymmetric spine synapse loss in PFC of PCP-treated rats. Olanzapine had no significant effect on spine synapse number in saline-treated controls. These studies demonstrate that the effect of PCP on asymmetric spine synapse number in PFC lasts at least 4 weeks in this model. This spine synapse loss in PFC is reversed by acute treatment with olanzapine, and this reversal is maintained by chronic oral treatment, paralleling the time course of the restoration of the dopamine deficit, and normalization of cognitive function produced by olanzapine.
authors.affiliation: Laboratory of Neuropsychopharmacology, Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511, USA. john.elsworth@yale.edu
authors.forename: John D
authors.initials: JD
authors.lastname: Elsworth
authors.forename: Bret A
authors.initials: BA
authors.lastname: Morrow
authors.forename: Tibor
authors.initials: T
authors.lastname: Hajszan
authors.forename: Csaba
authors.initials: C
authors.lastname: Leranth
authors.forename: Robert H
authors.initials: RH
authors.lastname: Roth
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000008:administration & dosage*; D002452:Cell Count / Q000379:methods; D049229:Dendritic Spines / Q000187:drug effects* / Q000502:physiology; D004334:Drug Administration Schedule; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D000077152:Olanzapine; D010622:Phencyclidine / Q000633:toxicity*; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D016896:Treatment Outcome
chemical_list: D001569:Benzodiazepines; D010622:Phencyclidine; D000077152:Olanzapine