Sex-Dependent Up-Regulation of Two Splicing Factors, Psf and Srp20, during Hippocampal Memory Formation

• Published in: Learning & memory (Cold Spring Harbor, N.Y.) N.Y.), 2007-10, Vol.14 (10), p.693-702
• Main Authors: Antunes-Martins, Ana, Mizuno, Keiko, Irvine, Elaine E, Lepicard, Eve M, Giese, K. Peter
• Format: Article
• Language: English
• Subjects: Alternative Splicing - genetics; Animals; Avoidance Learning - physiology; Behavioral psychophysiology; Biological and medical sciences; Brain; Calcium-Calmodulin-Dependent Protein Kinase Kinase; Conditioning; Conditioning, Classical - physiology; Fear; Female; Females; Fundamental and applied biological sciences. Psychology; Gender Differences; Gene Expression Profiling; Gene Expression Regulation; Genetics; Hippocampus - metabolism; Long Term Memory; Male; Males; Maze Learning - physiology; Memory - physiology; Mice; Nerve Tissue Proteins - biosynthesis; Nerve Tissue Proteins - genetics; Protein-Serine-Threonine Kinases - deficiency; Protein-Serine-Threonine Kinases - genetics; Psychology. Psychoanalysis. Psychiatry; Psychology. Psychophysiology; PTB-Associated Splicing Factor; Puberty; RNA, Messenger - biosynthesis; RNA-Binding Proteins - biosynthesis; RNA-Binding Proteins - genetics; Serine-Arginine Splicing Factors; Sex Characteristics; Sexual Maturation; Spatial Ability
• ISSN: 1072-0502; 1549-5485
• DOI: 10.1101/lm.640307

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[superscript 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 CaMKK[beta]-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 CaMKK[beta]-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. (Contains 6 figures.)