Loss of asymmetric spine synapses in dorsolateral prefrontal cortex of cognitively impaired phencyclidine-treated monkeys

Abstract

Schizophrenia patients, long-term abusers of phencyclidine (PCP), and monkeys treated with PCP all exhibit enduring cognitive deficits. Evidence indicates that loss of prefrontal cortex spine synapses results in cognitive dysfunction, suggesting the presence of synaptic pathology in the monkey PCP model; however, there is no direct evidence of such changes. In this study we use the monkey PCP model of schizophrenia to investigate at the ultrastructural level whether remodelling of dorsolateral prefrontal cortex (DLPFC) asymmetric spine synapses occurs following PCP. Subchronic PCP treatment resulted in a decrease in the number of asymmetric spine synapses, which was greater in layer II/III than layer V of DLPFC, compared to vehicle-treated controls. This decrease may contribute to PCP-induced cognitive dysfunction in the non-human primate model and perhaps in schizophrenia. Thus, the synapse loss in the PCP model provides a novel target for the development of potential treatments of cognitive dysfunction in this model and in schizophrenia.

Figure 1

Representative electron micrographs taken from layer II/III of the dorsolateral prefrontal cortex, demonstrating spine synapses (arrowheads) in vehicle-treated (panel a) and phencyclidine-treated (panel b) monkeys. Scale bar is 1 micrometer.

Figure 2

Loss of asymmetric spine synapses following phencyclidine treatment in dorsolateral prefrontal cortex in layers II/III (panel a) and layer V (panel b). A repeated measures ANOVA (treatment × layer) showed a significant effect of treatment (PCP or saline) [F(1,6) = 67.1, p < 0.0005) indicated by *, and layer [F(1,6) = 22.7, p < 0.005) on asymmetric synapse number in DLPFC and a significant interaction between these factors (F(1,6) = 9.0, p < 0.02). Contrast analysis (SuperANOVA, Abacus Concepts, Inc., Berkeley, CA) revealed a significant difference between number of asymmetric synapses in layer II/III and layer V in PCP-treated monkeys [F(1) =30.0, p < 0.002) indicated by †, but no significant difference in saline-treated control monkeys [F(1) = 1.5, p=0.25)].