Sex-dependent up-regulation of two splicing factors, Psf and Srp20, during hippocampal memory formation.
Gene transcription is required for long-term memory (LTM) formation. LTM formation is impaired in a male-specific manner in mice lacking either of the two Ca(2+)/calmodulin-dependent kinase kinase (Camkk) genes. Since altered transcription was suggested to cause these impairments in LTM formation, we used microarrays to screen for CaMKKbeta-dependent gene expression changes. Here we show that the hippocampal mRNA expression of two splicing factors, splicing factor arginine/serine-rich 3 (Sfrs3/Srp20) and polypyrimidine tract-binding protein-associated splicing factor (Psf), is altered in CaMKKbeta-deficient males. In wild-type (WT) mice, the basal expression level in the hippocampus is higher in males than in females, and the sex difference in Srp20 expression is detectable before puberty. Training in two hippocampus-dependent learning tasks, the spatial version of the Morris water maze (MWM) and background contextual fear conditioning, increases the hippocampal mRNA expression of both splicing factors in WT males. However, the increase in Srp20 mRNA expression occurs only in males and not in females, whereas the up-regulation of Psf expression occurs in both sexes. Importantly, control experiments demonstrate that the up-regulation of both splicing factors is specific for the learned associations after contextual fear conditioning. In summary, we provide the first evidence for a regulation of splicing factors during LTM formation and we suggest that alternative splicing contributes to sex differences in LTM formation.
Antunes-Martins
Ana
A
Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, United Kingdom.
Mizuno
Keiko
K
Irvine
Elaine E
EE
Lepicard
Eve M
EM
Giese
K Peter
KP
D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D001362:Avoidance Learning / Q000502:physiology*; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D003214:Conditioning, Classical / Q000502:physiology; D005239:Fear; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D018782:Maze Learning / Q000502:physiology*; D008568:Memory / Q000502:physiology*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D000072670:PTB-Associated Splicing Factor; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D016601:RNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D000068103:Serine-Arginine Splicing Factors; D012727:Sex Characteristics; D012741:Sexual Maturation
D009419:Nerve Tissue Proteins; D000072670:PTB-Associated Splicing Factor; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C106161:Srsf3 protein, mouse; D000068103:Serine-Arginine Splicing Factors; D017346:Protein Serine-Threonine Kinases; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase