Dysregulation of Brain-Derived Neurotrophic Factor Expression and Neurosecretory Function inMecp2Null Mice

Abstract

Disruptions in brain-derived neurotrophic factor (BDNF) expression are proposed to contribute to the molecular pathogenesis of Rett syndrome (RTT), a severe neurological disorder caused by loss-of-function mutations in methyl-CpG-binding protein-2 (MeCP2). Although MeCP2 is a transcriptional regulator of BDNF, it is unknown how MeCP2 mutations affect transynaptic BDNF signaling. Our findings demonstrate an early, abnormal neurosecretory phenotype in MeCP2-deficient neurons characterized by significant increases in the percentage of cellular BDNF content available for release. However, loss of MeCP2 also results in deficits in total cell BDNF content that are developmentally regulated in a cell-type-specific manner. Thus, the net effect of MeCP2 loss on absolute BDNF secretion changes with age and is determined by both the amount of BDNF available for release and progressive declines in total cellular BDNF. We propose, therefore, that loss of MeCP2 function disrupts transynaptic BDNF signaling by perturbing the normal balance between BDNF protein levels and secretion. However, mutant neurons are capable of secreting wild-type levels of BDNF in response to high-frequency electrical stimulation. In addition, we found elevated exocytic function in Mecp2 Ϫ/y adrenal chromaffin cells, indicating that the Mecp2 null mutation is associated with alterations of neurosecretion that are not restricted to BDNF. These findings are the first examples of abnormal neuropeptide and catecholamine secretion in a mouse model of RTT.

Advances in behavioral genetics: mouse models of autism

“…345 There are also reports that Mecp2 plays a role in the regulation of Bdnf levels. 134,201,202 Reduction in the levels of Bdnf exacerbates the phenotype of both the Rett syndrome-model mouse 346 and the Sert deletion line. [208][209][210] In the Rett syndrome-model mouse, Bdnf overexpression with an inducible Bdnf transgene leads to partial correction of abnormalities linked to loss of Mecp2 function.…”

“…[192][193][194] Work with mouse lines characterized by deficient Bdnf has shown that these trophic effects are important for normal serotonergic neurotransmission. [195][196][197][198][199][200] In addition, several lines of evidence have provided support for a role of Mecp2 in the regulation of activity-dependent transcription of Bdnf, 134,201,202 suggesting that alterations in 5-HT signaling could arise from deficient Mecp2 function, through dysregulation of Bdnf. Bdnf-null mice die soon after birth, but mutants have been developed with conditional disruption of Bdnf, limited to either the prenatal or postnatal period.…”

MECP2 disorders: from the clinic to mice and back

“…Initial attempts to rescue Rett mouse models focused on reversing the putative damage caused by the transcriptional changes observed in the KO animals. KO animals exhibit decreased RNA and protein levels of brain-derived neurotrophic factor (BDNF) (89,121,122). Given the importance of BDNF as a neuronal growth factor, attempts have been made to normalize the levels of BDNF in KO animals genetically and pharmacologically.…”

Brain-Derived Neurotrophic Factor Expression and Respiratory Function Improve after Ampakine Treatment in a Mouse Model of Rett Syndrome

“…For example, Mecp2 null mice exhibit progressive deficits in BDNF levels after birth (Chang et al, 2006;Wang et al, 2006), and genetic restoration of BDNF in the forebrain improves somatomotor function and extends lifespan (Chang et al, 2006). Moreover, neural structures important for cardiorespiratory control, including the nodose cranial sensory ganglia (NGs) and brainstem, exhibit the earliest and most significant known deficits in BDNF expression in the Mecp2 null mouse brain (Wang et al, 2006). Because BDNF is required for the development of NG and brainstem respiratory neurons, as well as breathing (Katz, 2005), we hypothesize that BDNF deficits contribute to the RTTlike respiratory phenotype of Mecp2 null mice.…”

“…To test this hypothesis, we examined BDNF expression in NG neurons cultured under depolarizing and nondepolarizing conditions. Because the NG comprises a single neuronal cell type (sensory neurons) and exhibits the Mecp2 null BDNF phenotype in vitro as in vivo (Wang et al, 2006), it provides a simple model for exploring mechanisms that underlie BDNF regulation by MeCP2. Our data indicate that Mecp2 null cells exhibit significantly lower levels of BDNF expression than wild type, under both depolarizing and nondepolarizing conditions.…”