Regulation of contextual fear conditioning by baseline and inducible septo-hippocampal cyclin-dependent kinase 5.
In this work, we confirm the novel role of cyclin-dependent kinase (Cdk) 5 in associative learning by demonstrating that injection of the Cdk5 inhibitor butyrolactone I into the lateral septum or hippocampus profoundly impaired context-dependent fear conditioning of C57BL/6J mice. However, unlike the inducible up-regulation of Cdk5 and its regulator p35 observed in Balb/c mice, high baseline levels, which were not affected by fear conditioning, were found in C57BL/6J mice. Surprisingly, microinjections of butyrolactone I into the lateral septum or hippocampus significantly decreased baseline Cdk5 activity within the entire septo-hippocampal circuitry, suggesting a functional link between septal and hippocampal Cdk5 activity. Significantly higher levels of the transcription factor Sp4 in the septo-hippocampal system of C57BL/6J mice may account for the high baseline Cdk5/p35 production. On the other hand, the stronger cFos production observed in the lateral septum of fear conditioned Balb/c mice may be responsible, at least in part, for the inducible up-regulation of Cdk5 in this strain. These results suggest that the role of Cdk5 in memory consolidation is strain independent and functionally related to the septo-hippocampal circuitry. However, the molecular regulation of baseline and inducible Cdk5 protein might be different among individual mouse strains and possibly other species.
Fischer
André
A
Department of Molecular Neuroendocrinology, Max Planck Institute for Experimental Medicine, Hermann-Rein-Str. 3, 37075, Goettingen, Germany. fischer@mail.em.mpg.de
Sananbenesi
Farahnaz
F
Schrick
Christina
C
Spiess
Joachim
J
Radulovic
Jelena
J
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D003213:Conditioning, Psychological; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005239:Fear / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology*; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008845:Microinjections; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D011233:Precipitin Tests; D020665:Septum of Brain / Q000187:drug effects / Q000201:enzymology*; D013045:Species Specificity; D014157:Transcription Factors / Q000096:biosynthesis
D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; C089495:neuronal Cdk5 activator (p25-p35); C082868:butyrolactone I; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D018844:Cyclin-Dependent Kinases; D015107:4-Butyrolactone