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.
Key Words
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Article info
Publication history
Published online: October 31, 2008
Accepted:
August 20,
2008
Received in revised form:
August 20,
2008
Received:
October 4,
2007
Identification
Copyright
© 2008 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
