Maternal Behavior Regulates Benzodiazepine/GABAA Receptor Subunit Expression in Brain Regions Associated with Fear in BALB/c and C57BL/6 Mice

Abstract

Inbred strains of mice, such as BALB/cByJ and C57BL/6ByJ, have been used repeatedly to study genotype–phenotype relations. These strains differ on behavioral measures of fear. In novel environments, for example, BALB/c mice are substantially more neophobic than C57BL/6 animals. The benzodiazepine (BZ)/GABA_A receptor system has been proposed as a regulator of behavioral responses to stress, and BALB/c and C57BL/6 mice differ in BZ/GABA_A receptor binding. In the present study, we found increased BZ receptor levels in C57BL/6 mice in the central and basolateral nuclei of the amygdala as well as the locus coeruleus using either flunitrazepam (nonselective) or zolpidem (α1 subtype selective) as radioligands. Differences in receptor binding were most pronounced in the amygdala and locus coeruleus using [³H]zolpidem. C57BL/6 mice showed increased α1 mRNA levels in the locus coeuruleus compared to BALB/c mice. In addition, γ2 mRNA expression in BALB/c mice was decreased in the central nucleus of the amygdala to levels that were 2–2.5-fold lower than those of C57BL/6 mice. The results of an adoption study revealed that the biological offspring of C57BL/6 mothers fostered after birth to BALB/c dams showed decreased levels of γ2 mRNA expression in the central nucleus of the amygdala in comparison to peers fostered to other C57BL/6 mothers (the reverse was found for the biological offspring of BALB/c mothers). In a step-down exploration paradigm, BALB/cByJ mice crossfostered onto a C57BL/6ByJ dam expressed reduced anxiety responses. However, among C57BL/6ByJ mice, the relatively low levels of anxiety ordinarily evident were not increased when mice of this strain were reared by a BALB/cByJ dam. These preliminary findings suggest that the strain differences in the BZ/GABA_A receptor system occur, at least in part, as a function of parental care. Such findings may reflect a mammalian example of an indirect genetic effect mediated by maternal care.