Neonatal exposure to low dose corticosterone persistently modulates hippocampal mineralocorticoid receptor expression and improves locomotor/exploratory behaviour in a mouse model of Rett syndrome.
Rett syndrome (RTT) is a pervasive neurodevelopmental disorder, primarily affecting girls. RTT causes a wide variety of debilitating symptoms and no cure currently exists. Mouse models bearing mutations in the Mecp2 gene recapitulate most physiological and behavioural RTT-related abnormalities. Stimulating neonatal environments (e.g. brief maternal separations or maternal low-dose corticosterone supplementation) reduce stress and fear responses at adulthood. The present study investigated whether impacting early in development the hypothalamic-pituitary-adrenal axis, by exposing Mecp2-308 mutant pups to a low dose of corticosterone (50 µg/ml, during the 1st week of life) may contrast RTT-related abnormalities in neuroendocrine regulation and behavioural adaptation at adulthood. In line with previous reports, when fully symptomatic, MeCP2-308 mice showed a reduction in the regular nocturnal hyperactivity in the home-cage and increased anxiety-like behaviours and plasma corticosterone (CORT) levels in response to restraint stress. An abnormal elevation in mRNA levels of mineralocorticoid receptors (MR) and BDNF gene was also evident in the hippocampus of fully symptomatic mutant mice. Neonatal CORT modulated MR gene expression and behavioural reactivity towards a novel object, also restoring wt-like levels of locomotor/exploratory behaviour in mutant mice. Enhanced sensitivity to the neonatal treatment (in terms of increase in GR and MR mRNA levels), was also evident in the hippocampus of MeCP2-308 mice compared to wt littermates. Present results corroborate the hypothesis that targeting the glucocorticoid system may prove valid in contrasting at least some of the RTT-related symptoms and provide evidence that pharmacological interventions during critical early time windows can persistently improve the behavioural phenotype of RTT mice. Current data also support the emerging role played by Mecp2 in mediating the epigenetic programming induced by early life events and indicate that, in the absence of functional MeCP2, programming of the central nervous system in response to early environmental stimuli is abnormally regulated. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'.
Sect. Behavioural Neuroscience, Dept. Cell Biology & Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
Bianca
B
De Filippis
Laura
L
Ricceri
Andrea
A
Fuso
Giovanni
G
Laviola
D000818:Animals; D002940:Circadian Rhythm / Q000187:drug effects / Q000235:genetics; D003345:Corticosterone / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects* / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects* / Q000235:genetics; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism*; D012149:Restraint, Physical; D015518:Rett Syndrome / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological / Q000502:physiology; D013315:Stress, Psychological / Q000235:genetics / Q000378:metabolism
D018161:Receptors, Mineralocorticoid; D003345:Corticosterone