Analysis of Kalirin-7 Knockout Mice Reveals Different Effects in Female Mice

Abstract

Estradiol treatment of ovariectomized rodents is known to affect the morphology of dendritic spines and produce behavioral and cognitive effects. Kalirin-7 (Kal7), a postsynaptic density (PSD)-localized Rho-guanine nucleotide exchange factor, is important for dendritic spine formation and stability. Male Kal7 knockout [Kal7(KO)] mice exhibit a number of abnormal behavioral and biochemical phenotypes. Given that chronic 17␤-estradiol (E2) replacement of ovariectomized rats enhanced Kal7 expression in the hippocampus and primary hippocampal cultures, we assessed the behavioral and biochemical effects of chronic E2 treatment of ovariectomized female wild-type and Kal7(KO) mice. Both intact and ovariectomized Kal7(KO) female mice exhibited decreased anxiety-like behavior compared with the corresponding wild type in the elevated zero maze and were unaffected by E2 treatment. Chronic E2 decreased locomotor activity in the open field and enhanced performance in a passive-avoidance fear conditioning task, which were both unaffected by genotype. Kal7(KO) female mice engaged in significantly more object exploration, both familiar and novel, than did wild-type females. E2 enhanced the acute locomotor response to cocaine, with no significant effect of genotype. Similar to Kal7(KO) males, Kal7(KO) females had decreased levels of Nmethyl-D-aspartate receptor 2B in hippocampal PSD fractions with no effect of E2 treatment. The differing behavioral effects of Kal7 ablation in female and male mice may offer insight into the molecular underpinnings of these differences.

Brain Region and Isoform-Specific Phosphorylation Alters Kalirin SH2 Domain Interaction Sites and Calpain Sensitivity

“…Behavioral studies of mice lacking Kal7 (Kal7 KO ) revealed its essential role in fear-based learning and in the response to chronic cocaine 13-16 . KalSR KO (full Kalirin knockout) mice show similar behavioral and drug-dependent deficits in addition to endocrine, cardiac and skeletal deficiencies 1 7-19 .…”

Elimination of Kalrn expression in POMC cells reduces anxiety-like behavior and contextual fear learning

“…While some of these abnormalities are shared with Kal7 KO mice, others are not (Kiraly et al 2010;Kiraly et al 2013;Lemtiri-Chlieh et al 2011;Ma et al 2008;Mazzone et al 2012); shared traits, such as the decrease in anxiety-like behavior and impaired contextual fear learning, may reflect the loss of Kal7. Since several of the traits exhibited by KalSR KO mice involve aberrant pituitary hormone secretion and several behavioral phenotypes suggest hypothalamic-pituitary-adrenal involvement, we chose to test the effects of eliminating Kalirin expression only in cells which express POMC at some time during development or in adulthood.…”

“…4). Several of the deficits identified in Kalirin knockout mice are also sex-specific (Mandela et al 2012;Mazzone et al 2012). …”

“…Hippocampal pyramidal neurons help drive the hypothalamic-pituitary adrenal axis during stress but are suppressed by chronic exposure to corticosterone (Bhargava et al 2000;Dallman et al 1987;Young et al 1990). Hippocampal Kalirin expression is up-regulated by estrogens in females (Ma et al 2011;Mazzone et al 2012), so it was reasonable to expect a sex-based difference in the corticosterone released after major stress (Fig.4A) and a major effect of Kalirin ablation which might show a sex difference (Fig.4A). …”

“…Another possible explanation involves knockout of Kal7 in the widespread population of cells that produced POMC at some time during development - hippocampus, cortex, and amygdala are obvious candidates. Based on what is known about the role of Kal7 in other neurons, the absence of Kal7 presumably affects synapses with excitatory inputs onto functionally compromised dendritic spines of neurons no longer expressing Kalirin (Kiraly et al 2011;Kiraly et al 2010;Kiraly et al 2013;Lemtiri-Chlieh et al 2011;Ma et al 2008;Mazzone et al 2012). There are major projections from the arcuate nucleus of endorphin- and melanotropin-containing fibers into the amygdala, hippocampus and cortex which could all be altered by depressed Kalirin levels (Balthasar 2006;Herman et al 2003;King and Hentges 2011;Vermetten and Bremner 2002).…”