Prenatal one-carbon metabolism dysregulation programs schizophrenia-like deficits.

The methionine-folate cycle-dependent one-carbon metabolism is implicated in the pathophysiology of schizophrenia. Since schizophrenia is a developmental disorder, we examined the effects that perturbation of the one-carbon metabolism during gestation has on mice progeny. Pregnant mice were administered methionine equivalent to double their daily intake during the last week of gestation. Their progeny (MET mice) exhibited schizophrenia-like social deficits, cognitive impairments and elevated stereotypy, decreased neurogenesis and synaptic plasticity, and abnormally reduced local excitatory synaptic connections in CA1 neurons. Neural transcript expression of only one gene, encoding the Npas4 transcription factor, was >twofold altered (downregulated) in MET mice; strikingly, similar Npas4 downregulation occurred in the prefrontal cortex of human patients with schizophrenia. Finally, therapeutic actions of typical (haloperidol) and atypical (clozapine) antipsychotics in MET mice mimicked effects in human schizophrenia patients. Our data support the validity of MET mice as a model for schizophrenia, and uncover methionine metabolism as a potential preventive and/or therapeutic target

Prenatal one-carbon metabolism dysregulation programs schizophrenia-like deficits.

The methionine-folate cycle-dependent one-carbon metabolism is implicated in the pathophysiology of schizophrenia. Since schizophrenia is a developmental disorder, we examined the effects that perturbation of the one-carbon metabolism during gestation has on mice progeny. Pregnant mice were administered methionine equivalent to double their daily intake during the last week of gestation. Their progeny (MET mice) exhibited schizophrenia-like social deficits, cognitive impairments and elevated stereotypy, decreased neurogenesis and synaptic plasticity, and abnormally reduced local excitatory synaptic connections in CA1 neurons. Neural transcript expression of only one gene, encoding the Npas4 transcription factor, was >twofold altered (downregulated) in MET mice; strikingly, similar Npas4 downregulation occurred in the prefrontal cortex of human patients with schizophrenia. Finally, therapeutic actions of typical (haloperidol) and atypical (clozapine) antipsychotics in MET mice mimicked effects in human schizophrenia patients. Our data support the validity of MET mice as a model for schizophrenia, and uncover methionine metabolism as a potential preventive and/or therapeutic target

Medicinal Chemistry, Pharmacology, and Biological Actions of Peptide Ligands Selective for the Nociceptin/Orphanin FQ Receptor

Nociceptin/orphanin FQ (N/OFQ; FGGFTGARKSARKLANQ) was identified via reverse pharmacology strategies as the endogenous ligand of a previously orphan GPCR now referred to as N/OFQ peptide (NOP) receptor. The N/OFQ – NOP receptor system is widely distributed in the nervous system where it modulates several different biological functions. Structure relationship studies performed on the N/OFQ sequence allowed to generate NOP selective ligands encompassing full and partial agonist as well as pure antagonist activity, to increase their potency, metabolic stability, and in vivo duration of action. These peptide NOP ligands were used to investigate the consequences of NOP receptor activation and block thus suggesting the possible therapeutic indications of drugs interacting with this receptor. Evidence coming from these studies, together with findings obtained with knockout animals and non peptide NOP ligands, suggests that the most promising indications for NOP antagonists are depression and Parkinson disease and for agonists anxiety, drug abuse, cough, and pain (after spinal administration). In addition, clinical studies demonstrated that intravesical instillation of N/OFQ elicits beneficial effects in patients with overactive bladder