Implication of neuronal Ca2+ -sensor protein VILIP-1 in the glutamate hypothesis of schizophrenia.
Post mortem studies in the hippocampus of schizophrenia patients revealed increased expression of neuronal Ca(2+)-sensor VILIP-1 (visinin-like protein) and enhanced co-localization with alpha4beta2 nAChR in interneurons. To study the pathological role of VILIP-1, particularly in interneurons, in the context of the glutamate hypothesis of schizophrenia, we have used ketamine-treated rats, a NMDA receptor hypofunction model, and hippocampal cultures as model systems for schizophrenia. Treatment with ketamine leads to enhanced VILIP-1 expression in interneurons in rat hippocampal CA1 region. In cultures glutamate treatment led to an increase in VILIP-1-positive interneurons, which is not dependent on NMDA receptor but metabotropic glutamate receptor activation. VILIP-1 mainly co-localizes with the interneuron marker calretinin, mGluR1alpha and the VILIP-1 interaction partner alpha4beta2 nAChR in hippocampal slices. Overexpression of VILIP-1 leads to enhanced nAChR-dependent inhibitory postsynaptic current (IPSC) generation by interneurons. This novel molecular link between the pathological role of mGluRs, VILIP-1 and its interaction partner alpha4beta2 nAChR by converging pathological glutamatergic and nicotinergic transmission may underlie cognitive impairments in schizophrenia.
Gierke
Paul
P
Signal Transduction Research Group, Neuroscience Research Center, Charité, Universitaetsmedizin Berlin, Germany.
Zhao
Congjian
C
Bernstein
Hans-Gert
HG
Noack
Cornelia
C
Anand
Rene
R
Heinemann
Uwe
U
Braunewell
Karl-Heinz
KH
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D018891:Dentate Gyrus / Q000378:metabolism; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007395:Interneurons / Q000378:metabolism / Q000473:pathology; D052139:Intracellular Calcium-Sensing Proteins / Q000378:metabolism*; D007649:Ketamine / Q000008:administration & dosage; D008297:Male; D051596:Neurocalcin / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism / Q000502:physiology; D011978:Receptors, Nicotinic / Q000378:metabolism; D012559:Schizophrenia / Q000378:metabolism* / Q000473:pathology
D052139:Intracellular Calcium-Sensing Proteins; D051596:Neurocalcin; D018094:Receptors, Metabotropic Glutamate; D011978:Receptors, Nicotinic; C496688:VSNL1 protein, human; C104077:metabotropic glutamate receptor type 1; C403531:nicotinic receptor alpha4beta2; D018698:Glutamic Acid; D007649:Ketamine; D002118:Calcium