Males Afraid, Females Brave

Abstract

There are different kinds of memories. In mice, differences have been noted in contextual fear memory formation and spatial memory formation, although both forms of memory appear to involve a calcium signal and the activation of calcium/calmodulin-dependent kinases (CaMKs). In mice, there are two isoforms of CaMK that have been implicated in memory formation (CaMKI and CaMKIV) and two upstream kinases that phosphorylate CaMK (CaM kinase kinases: CaMKKα and CaMKKβ). CaMKKβ has been implicated in spatial memory formation, and CaMKIV has been implicated in long-term potentiation and fear conditioning. Two groups, Blaeser et al . and Mizuno et al ., created mice deficient in CaMKKα function and found that the mice showed normal spatial memory, normal motor activity, and normal sensory perception; however, male mice were impaired in the formation of contextual fear memories. Synaptic transmission was not impaired in the CamKKα-deficient mice, nor was formation of hippocampal long-term potentiation. Blaeser et al . showed that, compared with wild-type mice, the CamKKα-deficient male mice exhibited decreased phosphorylation of CaMKIV and the transcriptional regulator CREB (a substrate of CaMKIV) in response to fear conditioning. Phosphorylation of CREB under basal conditions was increased in the mutant mice in certain brain regions; however, the fear-induced increases in phosphorylation were absent. Mizuno et al . investigated memory formation in both male and female mice deficient for CaMKKα and noted that females did not show impairment of contextual fear conditioning. (It was known that female mice tend to exhibit contextual fear conditioning to a lesser extent than do male mice.) In wild-type mice, contextual fear conditioning promoted an increase in brain-derived neurotrophic factor (BDNF) in males only and a decrease in BDNF in females (transcript abundance was measured by real-time polymerase chain reaction). In the CaMKKα-deficient mice, the increase in BDNF in males was compromised, but the decrease in females was unaffected. The gene encoding BDNF is a CREB target; however, expression of another gene regulated by CREB, the gene encoding nerve growth factor-inducible gene B (NGF-1B), was increased in response to fear conditioning in both males and females and was not affected by lack of CaMKKα. Thus, in addition to specific forms of memory requiring specific signaling cascades, there is an additional gender-specific layer of regulation. F. Blaeser, M. J. Sanders, N. Truong, S. Ko, L. J. Wu, D. F. Wozniak. M. S. Fanselow, M. Zhuo, T. A. Chatila, Long-term memory deficits in Pavlovian fear conditioning in Ca 2+ /calmodulin kinase kinase α-deficient mice. Mol. Cell. Biol. 26 , 9105-9115 (2006). [Abstract] [Full Text] K. Mizuno, L. Ris, A. Sánchez-Capelo, E. Godaux, K. P. Giese, Ca 2+ /calmodulin kinase kinase α is dispensable for brain development but is required for distinct memories in male, though not in female, mice. Mol. Cell. Biol. 26 , 9094-9104 (2006). [Abstract] [Full Text]