Deficits of Hippocampal RNA Editing and Social Interaction Resulting from Prenatal Stress are Mitigated by Clozapine

Abstract

AbstractBackgroundNeurodevelopmental deficits resulting from prenatal stress are associated with neurological disorders that include deficits of social behavior, such as schizophrenia1 and autism2–7. Studies of human brain and animal models indicate that an epitranscriptomic process known as ‘RNA editing’ contributes to the pathophysiology of these disorders, which occur more frequently in males than in females8–20. RNA editing plays an important role in brain development through its modification of excitatory and inhibitory neurotransmission21.MethodsWe exposed pregnant mice to restraint stress three times daily during gestational weeks 2 and 3. We treated the adult male offspring with haloperidol (1mg/kg), clozapine (5mg/kg) or saline twice daily for 5 days. Subsequently we measured social interaction behavior (SI) and locomotor activity, followed by next-generation sequencing analyses of hippocampal RNA editing.ResultsMice exposed to PRS exhibited reduced SI, which correlated with hippocampal RNA editing of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits GluA2, GluA3 and GluA4, the potassium channel Kv1.1, the calcium channel subunit Cav1.3, calcium-dependent secretion activator (CAPS-1) and the calcium-dependent cell adhesion protein, cadherin 22 (CDH22). Treatment with clozapine, but not haloperidol, normalized SI behavior, and selectively reduced the deficits in GluA2 RNA editing in PRS mice.ConclusionsRNA editing may contribute to impaired hippocampal function after exposure to PRS. The efficacy of clozapine in improving SI behavior may include indirect stimulation of GluA2 RNA editing in the hippocampus. Although these data are from male mice and not humans, the results suggest a new molecular pathway by which PRS leads to life-long impairments of hippocampal function.