Age-dependent microRNA control of synaptic plasticity in 22q11 deletion syndrome and schizophrenia.
The 22q11 deletion syndrome (22q11DS) is characterized by multiple physical and psychiatric abnormalities and is caused by the hemizygous deletion of a 1.5-3 Mb region of chromosome 22. It constitutes one of the strongest known genetic risks for schizophrenia; schizophrenia arises in as many as 30% of patients with 22q11DS during adolescence or early adulthood. A mouse model of 22q11DS displays an age-dependent increase in hippocampal long-term potentiation (LTP), a form of synaptic plasticity underlying learning and memory. The sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA2), which is responsible for loading Ca(2+) into the endoplasmic reticulum (ER), is elevated in this mouse model. The resulting increase in ER Ca(2+) load leads to enhanced neurotransmitter release and increased LTP. However, the mechanism by which the 22q11 microdeletion leads to SERCA2 overexpression and LTP increase has not been determined. Screening of multiple mutant mouse lines revealed that haploinsufficiency of Dgcr8, a microRNA (miRNA) biogenesis gene in the 22q11DS disease-critical region, causes age-dependent, synaptic SERCA2 overexpression and increased LTP. We found that miR-25 and miR-185, regulators of SERCA2, are depleted in mouse models of 22q11DS. Restoration of these miRNAs to presynaptic neurons rescues LTP in Dgcr8(+/-) mice. Finally, we show that SERCA2 is elevated in the brains of patients with schizophrenia, providing a link between mouse model findings and the human disease. We conclude that miRNA-dependent SERCA2 dysregulation is a pathogenic event in 22q11DS and schizophrenia.
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Laurie R
LR
Earls
R Gaines
RG
Fricke
Jing
J
Yu
Raymond B
RB
Berry
Lisa T
LT
Baldwin
Stanislav S
SS
Zakharenko
D058165:22q11 Deletion Syndrome / Q000201:enzymology / Q000235:genetics*; D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000502:physiology*; D009473:Neuronal Plasticity / Q000235:genetics*; D009924:Organ Culture Techniques; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000096:biosynthesis / Q000235:genetics*; D012559:Schizophrenia / Q000201:enzymology / Q000235:genetics*; D013569:Synapses / Q000201:enzymology / Q000235:genetics*
D035683:MicroRNAs; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506947:Atp2a2 protein, mouse