Insulin, IGF-1, and muscarinic agonists modulate schizophrenia-associated genes in human neuroblastoma cells.
BACKGROUND
Genes associated with energy metabolism are decreased in schizophrenia brain and human and rodent diabetic skeletal muscle. These and other similarities between diabetes and schizophrenia suggest that an insulin signaling deficit may underlie schizophrenia. We determined with human SH-SY5Y neuroblastoma and astrocyte cell lines whether insulin or other molecules could modulate genes opposite to their change reported in schizophrenia brain.


METHODS
Both cell lines were treated with insulin, insulin-like growth factor (IGF)-1, IGF-2, or brain-derived neurotrophic factor (BDNF). Genes whose expression was found with microarrays to be changed by insulin in a reciprocal manner to their change in schizophrenia were used in a 16-gene miniarray to identify small molecules that might mimic insulin.


RESULTS
Insulin phosphorylated its receptor in the neuroblastoma cells but not in astrocytes and, like IGF-1, increased ERK1/2 and Akt phosphorylation. Insulin and IGF-1 increased the expression of genes decreased in schizophrenia, including those involved in mitochondrial functions, glucose and energy metabolism, hydrogen ion transport, and synaptic function. These gene effects were confirmed and shown to be dose related with the 16-gene miniarrays. Most of 1940 pharmacologically unique compounds failed to alter gene expression, with the exception of muscarinic agonists, which mimicked insulin and IGF-1, and which were blocked by the muscarinic antagonists atropine and telenzepine.


CONCLUSIONS
Stimulation of muscarinic and insulin/IGF-1 receptors alter genes associated with metabolic and synaptic functions in a manner reciprocal to their changes in schizophrenia. Pharmacologic activation of these receptors may normalize genomic alterations in schizophrenia and better address root causes of this disease.
Altar
C Anthony
CA
Psychiatric Genomics, Inc., Gaithersburg, Maryland, USA.
Hunt
Rachel A
RA
Jurata
Linda W
LW
Webster
Maree J
MJ
Derby
Eric
E
Gallagher
Paul
P
Lemire
Andrew
A
Brockman
Jeffrey
J
Laeng
Pascal
P
D000328:Adult; D001714:Bipolar Disorder / Q000473:pathology; D001921:Brain; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002540:Cerebral Cortex; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007328:Insulin / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D018721:Muscarinic Agonists / Q000494:pharmacology*; D009447:Neuroblastoma; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology
D007328:Insulin; D018721:Muscarinic Agonists; D007334:Insulin-Like Growth Factor I; D011972:Receptor, Insulin