Abstract
Risk factors for psychiatric disorders have traditionally been classified as genetic or environmental. Risk (candidate) genes, although typically possessing small effects, represent a clear starting point to elucidate downstream cellular/molecular pathways of disease. Environmental effects, especially during development, can also lead to altered behavior and increased risk for disease. An important environmental factor is the mother, demonstrated by the negative effects elicited by maternal gestational stress and altered maternal care. These maternal effects can also have a genetic basis (e.g., maternal genetic variability and mutations). The focus of this review is “maternal genotype effects” that influence the emotional development of the offspring resulting in life-long psychiatric disease-like phenotypes. We have recently found that genetic inactivation of the serotonin 1A receptor (5-HT1AR) and the fmr1 gene (encoding the fragile X mental retardation protein) in mouse dams results in psychiatric disease-like phenotypes in their genetically unaffected offspring. 5-HT1AR deficiency in dams results in anxiety and increased stress responsiveness in their offspring. Offspring of 5-HT1AR deficient dams display altered development of the hippocampus, which could be linked to their anxiety-like phenotype. Maternal inactivation of fmr1, like its inactivation in the offspring, results in a hyperactivity-like condition and is associated with receptor alterations in the striatum. These data indicate a high sensitivity of the offspring to maternal mutations and suggest that maternal genotype effects can increase the impact of genetic risk factors in a population by increasing the risk of the genetically normal offspring as well as by enhancing the effects of offspring mutations.
Highlights
Risk factors for psychiatric disorders have traditionally been classified as genetic or environmental
Animal models can help identify mechanisms underlying maternal genotype effects an altered prenatal environment due to maternal genetic variability has been shown as a risk factor in psychiatric diseases such as autism and attention deficit hyperactivity disorder (ADHD) (Williams et al, 2007; Halmoy et al, 2011), the underlying disease mechanisms are difficult to identify because of the limitations associated with human studies
To demonstrate the feasibility of mouse models in studying maternal genotype effects and their mechanisms, we present our research on two maternal mutations that alter specific behavioral phenotypes and correlated cellular or pharmacologic properties in the genetically unaffected offspring
Summary
Maternal genotype effects could significantly contribute to the high heritability of common disorders including psychiatric diseases. We recently showed that partial or complete 5-HT1A receptor deficiency in Swiss Webster (SW) mouse dams can cause increased anxiety-related behavior and enhanced stress reactivity in their offspring, independently of offspring genotype (Gleason et al, 2010; Figure 1) Genetically WT offspring of 5-HT1A receptor deficient mice displayed increased anxiety-related behavior in the elevated plus maze. We demonstrated that maternal 5-HT1A receptor deficiency leads to reduced immobility time in the Porsolt Forced Swim Test, which can be interpreted as a lack of normal coping skills and an increase in reactivity to inescapable stress The development of this phenotype is independent of offspring genotype and requires both prenatal and postnatal maternal receptor deficit, as shown by embryo transfer and cross-fostering experiments. We identified several developmental changes that correlate with later life anxiety-related behavior, including an increased volume of the ventral granule cell layer (GCL) during the first postnatal week, which normalized by the age of 4 weeks
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