title: Alterations in the expression of neuronal chloride transporters may contribute to schizophrenia.
abstract: During brain development, neuronal stem cells and immature neurons express high and low levels of, respectively, the Cl(-) transporters NKCC1 and KCC2, which results in high intracellular Cl(-) concentrations. Under these circumstances chloride-flux through the GABA-A channel is from intracellular to extracellular and consequently GABA depolarizes rather than hyperpolarizes immature cells. This excitatory response is essential for neurodevelopment since it affects proliferation of the neuronal progenitor pool, neuronal differentiation, dendrite and synapse formation and integration into the existing neuronal network. In animal experiments, seizures were found to increase NKCC1 expression, lower the KCC2 expression and accelerate neuronal differentiation. An increased expression of NKCC1 and mutations of the gene have been associated with schizophrenia. Stimulation of nicotinic α-7 receptors on mouse hippocampal neurons increases the expression of KCC2. A microdeletion in the genomic area 15q13-14 containing the nicotine α7 receptor has been described in patients with mental retardation, schizophrenia and juvenile epilepsy. It is conceivable that haplotype-insufficiency of the nicotinic α7 receptor might lead to a reduction in KCC2 protein levels. The data indicate that all three schizophrenia risk factors, i.e. seizures, mutations in NKCC1 and nicotinic α-7 receptors haplotype-insufficiency contribute to higher intracellular Cl(-) concentrations, increased neuronal excitability and accelerated neuronal differentiation. Since also several other genetic risk factors for schizophrenia seem to accelerate neuronal maturation, it is hypothesized that the structural, cognitive and behavioral deficits of schizophrenia are caused be a too fast brain maturation process.
authors.affiliation: Novartis Pharma AG, Novartis Institutes of Biomedical Research Basel, WSJ-386.11.40, Postfach, CH-4002 Basel, Switzerland. hans.kalkman@novartis.com
authors.forename: Hans O
authors.initials: HO
authors.lastname: Kalkman
mesh_terms: D000367:Age Factors; D000818:Animals; D002712:Chlorides / Q000378:metabolism; D004827:Epilepsy / Q000150:complications / Q000378:metabolism*; D006801:Humans; D051379:Mice; D058953:Neural Stem Cells / Q000502:physiology*; D012307:Risk Factors; D012559:Schizophrenia / Q000150:complications / Q000235:genetics* / Q000378:metabolism*; D012640:Seizures / Q000150:complications / Q000378:metabolism*; D028021:Sodium-Potassium-Chloride Symporters / Q000235:genetics / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D002712:Chlorides; D028021:Sodium-Potassium-Chloride Symporters; D005680:gamma-Aminobutyric Acid