Schizophrenia: a neurodevelopmental disorder--integrative genomic hypothesis and therapeutic implications from a transgenic mouse model.

Abstract

Schizophrenia is a neurodevelopmental disorder featuring complex aberrations in the structure, wiring, and chemistry of multiple neuronal systems. The abnormal developmental trajectory of the brain appears to be established during gestation, long before clinical symptoms of the disease appear in early adult life. Many genes are associated with schizophrenia, however, altered expression of no one gene has been shown to be present in a majority of schizophrenia patients. How does altered expression of such a variety of genes lead to the complex set of abnormalities observed in the schizophrenic brain? We hypothesize that the protein products of these genes converge on common neurodevelopmental pathways that affect the development of multiple neural circuits and neurotransmitter systems. One such neurodevelopmental pathway is Integrative Nuclear FGFR1 Signaling (INFS). INFS integrates diverse neurogenic signals that direct the postmitotic development of embryonic stem cells, neural progenitors and immature neurons, by direct gene reprogramming. Additionally, FGFR1 and its partner proteins link multiple upstream pathways in which schizophrenia-linked genes are known to function and interact directly with those genes. A th-fgfr1(tk-) transgenic mouse with impaired FGF receptor signaling establishes a number of important characteristics that mimic human schizophrenia - a neurodevelopmental origin, anatomical abnormalities at birth, a delayed onset of behavioral symptoms, deficits across multiple domains of the disorder and symptom improvement with typical and atypical antipsychotics, 5-HT antagonists, and nicotinic receptor agonists. Our research suggests that altered FGF receptor signaling plays a central role in the developmental abnormalities underlying schizophrenia and that nicotinic agonists are an effective class of compounds for the treatment of schizophrenia.

• Authors: M K Stachowiak, A Kucinski, R Curl, C Syposs, Y Yang, S Narla, C Terranova, D Prokop, I Klejbor, M Bencherif, B Birkaya, T Corso, A Parikh, E S Tzanakakis, S Wersinger, E K Stachowiak
• Journal: Schizophrenia research (Schizophr Res) Vol. 143 Issue 2-3 Pg. 367-76 (Feb 2013) ISSN: 1573-2509 [Electronic] Netherlands
• PMID: 23231877 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2012 Elsevier B.V. All rights reserved.

Topics

• Animals
• Disease Models, Animal
• Genomics (methods, trends)
• Humans
• Mice
• Schizophrenia (genetics, pathology, therapy)