Title: Novel Insight into Cholinergic Factors Associated with Schizophrenia and Autoimmunity
Volume: 6
Issue: 4
Author(s): Leonor Sterin-Borda*Enri Borda
Affiliation:
- Catedra de Farmacologia, Facultad de Odontologia, Universidad de Buenos Aires, Marcelo T. de Alvear 2142 - Piso 4to. Sector B, 1122 - Buenos Aires,Argentina
Keywords:
Cholinergic system, autoantibodies, schizophrenia disease, muscarinic receptor, cerebral frontal cortex, biological
effects, ELISA assay, binding assay.
Abstract: Schizophrenia affects 1% of the world`s population, but its cause remains obscure. Numerous theories have been proposed regarding the etiology of schizophrenia, ranging from neurodegenerative, autoimmune processes, neurotransmitter abnormalities to inflammation. Here, we propose an integrative view of autoimmune processes and neurotransmitter dysregulation in schizophrenia. We focus on the role of serum autoantibodies against cerebral muscarinic cholinergic receptors (mAChR) as a neuroimmune factor in the etiology of schizophrenia. We describe the presence of circulating antibodies from patients with paranoid schizophrenia, that interact with mAChRs of cerebral frontal cortex neural and glial cells. The antibodies can inhibit irreversible binding of the specific mAChR radioligand. We have demonstrated with synthetic peptides that these autoantibodies react against the second extracellular loop of human neural M1 mAChR and glial M2 mAChR. Also, the corresponding affinity-purified anti-peptide antibody displays an agonisticlike activity that is associated with specific M1 and M2 receptor activation. We have established that anti-mAChR autoantibodies appear to interpose in crosstalk between neurons and glia, and therefore, could be involved in negative/positive symptoms or inflammatory abnormalities associated with schizophrenia. M1 or M2 mAChR activation by autoantibodies can give conflicting messages. Chronic autoantibody fixation on postsynaptic neuronal M1 mAChR results in receptor downregulation, uncoupled to Gq protein, which stabilizes phospholipase C activity, and interferes with cognitive function (including attention, learning and memory) and alters neuronal plasticity, which causes negative symptoms. On the contrary, the antibody fixation on. presynaptic glia M2 mAChR inhibits the agonist action determined that the glia loss the negative control on excitatory neurotransmitter release (dopamine and glutamate). Therefore, the antibodies could induce loss of glial physiological buffering function, which causes differential exposure to positive symptoms. Furthermore, the antibody with agonistic activity on glial M1 mAChR contributes to neuro-inflammatory activity, which triggers the production of NO (Nitric Oxide), PGE2 (Prostaglandin E2) and MMP-3 (Metalloproteinase-3) via induction of COX-1(Ciclooxygenase-1) and iNOS(inducible Nitric oxide syntase) gene expression and activity. We have evidence that supports the hypothesis that alteration of the immune system is involved in the pathogenesis of schizophrenia, and that muscarinic receptors could represent promising novel targets for the treatment of the disease.
