title: Potential opposite roles of the extracellular signal-regulated kinase (ERK) pathway in autism spectrum and bipolar disorders.
abstract: Signal transduction from the synapse to the nucleus subsequently involves transient increases in synaptic Ca2+, activation of CaM kinases, activation of the GTPase Ras, activation of the ERK mitogen-activated protein kinase pathway, and finally GSK3 inhibition and CREB-activation. Genetic studies in autism have identified mutations and copy number variations in a number of genes involved in this synapse to nucleus signaling path. In particular, a gain of function mutation in the CACNA1C gene, deletions and disruption of the SYNGAP1 gene, a copy number variation encompassing the MAPK3 gene and a duplication of YWHAE indicate that in a subset of autism patients the ERK cascade is inappropriately activated. Predicted functional consequences of this hyperactivation would be an increase in complexity of the dendritic tree, and via inhibition of GSK3, a delayed circadian phase. The latter effect indeed fits the frequent sleep disturbances observed in autistic patients. Interestingly, the sleep disturbances in bipolar disorder patients are frequently characterized as phase advanced. A selective evaluation of genetic mutations in bipolar patients indicates that the activity of the ERK cascade, at least in a subset of patients, presumably is hypoactive. Thus, with respect to the ERK pathway, autism and bipolar disorder seem each other's counter pole.
authors.affiliation: Neuroscience Department, Novartis Institute of Biomedical Research, Building 386-14.22.15, CH-4002 Basel, Switzerland. hans.kalkman@novartis.com
authors.forename: Hans O
authors.initials: HO
authors.lastname: Kalkman
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000201:enzymology* / Q000235:genetics; D001714:Bipolar Disorder / Q000201:enzymology* / Q000235:genetics; D002940:Circadian Rhythm / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009154:Mutation / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases