Prenatal cocaine exposure impairs cognitive function of progeny via insulin growth factor II epigenetic regulation.

Abstract:

:Studies have showed that prenatal cocaine exposure (PCOC) can impair cognitive function and social behavior of the offspring; however, the mechanism underlying such effect is poorly understood. Insulin-like growth factor II (Igf-II), an imprinted gene, has a critical role in memory consolidation and enhancement. We hypothesized that epigenetic regulation of hippocampal Igf-II may attribute to the cognitive deficits of PCOC offspring. We used Morris water maze and open-field task to test the cognitive function in PCOC offspring. The epigenetic alteration involved in hippocampal Igf-II expression deficit in PCOC offspring was studied by determining Igf-II methylation status, DNA methyltransferases (DNMT) expressions and L-methionine level. Moreover, IGF-II rescue experiments were performed and the downstream signalings were investigated in PCOC offspring. In behavioral tests, we observed impaired spatial learning and memory and increased anxiety in PCOC offspring; moreover, hippocampal IGF-II mRNA and protein expressions were significantly decreased. Hippocampal methylation of cytosine-phospho-guanine (CpG) dinucleotides in differentially methylated region (DMR) 2 of Igf-II was elevated in PCOC offspring, which may be driven by the upregulation of L-methionine and DNA methyltransferase (DNMT) 1. Importantly, intra-hippocampal injection of recombinant IGF-II reactivated the repressed calcium calmodulin kinase II α (CaMKIIα) and reversed cognitive deficits in PCOC offspring. Collectively, our findings suggest that cocaine exposure during pregnancy impairs cognitive function of offspring through epigenetic modification of Igf-II gene. Enhancing IGF-II signaling may represent a novel therapeutical strategy for cocaine-induced cognitive impairment.

journal_name

Neurobiol Dis

journal_title

Neurobiology of disease

authors

Zhao Q,Hou J,Chen B,Shao X,Zhu R,Bu Q,Gu H,Li Y,Zhang B,Du C,Fu D,Kong J,Luo L,Long H,Li H,Deng Y,Zhao Y,Cen X

doi

10.1016/j.nbd.2015.05.014

subject

Has Abstract

pub_date

2015-10-01 00:00:00

pages

54-65

eissn

0969-9961

issn

1095-953X

pii

S0969-9961(15)00188-6

journal_volume

82

pub_type

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