Cholinergic denervation attenuates phencyclidine-induced c-fos responses in rat cortical neurons.

The cortical cholinergic innervation, important for memory and cognition, may be involved in schizophrenia. Using the dissociative drug phencyclidine (PCP) to model schizophrenia in rats, researchers monitored rapid effects of low doses (2 and 3 mg/kg) on neural activation via c-fos mRNA in cortical areas. PCP induced c-fos mRNA across nearly all cortical areas without altering BDNF or Nogo receptor mRNA levels. Unilateral lesioning of cholinergic projections to the cortex by 192-IgG-saporin in the nucleus basalis magnocellularis caused a striking ipsilateral decrease in PCP-induced c-fos induction, restricted to denervated areas. The findings suggest that PCP acts through cholinergic input to activate cortical neurons, supporting a role for the cholinergic system in schizophrenia symptoms.

Study at a glance

Abstract

The cortical cholinergic innervation, which is important for memory and cognition, has been implicated in schizophrenia. To experimentally analyze such a possible role of the cholinergic system, we have used the dissociative drug phencyclidine (PCP), known to produce schizophrenia-like psychosis in humans, to model aspects of schizophrenia in rats. We previously showed that induced cortical cholinergic hypofunction leads to enhanced PCP-induced locomotor activity and attenuated social interaction. After PCP, rats lacking cortical cholinergic innervation also show impaired declarative memory. To directly study the role of the basalo-cortical cholinergic projections for PCP-induced neural activation in different cortical areas, we have now monitored the rapid (30 and 60 min) effects of low doses of PCP (2 and 3mg/kg) on neural activation as reflected by transcriptional activation of c-fos in cortical areas, using quantitative in situ hybridization. We find an almost pan-cortical neural induction of c-fos mRNA with doses of PCP low enough not to alter levels of either BDNF or Nogo receptor mRNA levels. Specific unilateral lesioning of the uncrossed cholinergic projections to the cortical mantle by 192-IgG-saporin immunotoxin delivery to nc basalis (NBM) caused a striking ipsilateral decrease of the PCP-induced cortical c-fos mRNA induction, restricted to areas which had become effectively denervated. Because PCP at low doses is unlikely to directly influence cortical neurons, we suggest that it acts by activation of the cholinergic input, which in turn leads to cortical c-fos mRNA increases. Our results are compatible with a role for the cholinergic system in symptoms of schizophrenia, by showing that the basalo-cortical cholinergic projections are needed in order for PCP to have full activating effects on cortical neurons.