Exogenous Brain-Derived Neurotrophic Factor Rescues Synaptic Dysfunction inMecp2-Null Mice

Abstract

Postnatal deficits in Brain-Derived Neurotrophic Factor (BDNF) are thought to contribute to pathogenesis of Rett syndrome (RTT), a progressive neurodevelopmental disorder caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). In Mecp2 null mice, a model of RTT, BDNF deficits are most pronounced in structures important for autonomic and respiratory control, functions that are severely affected in RTT patients. However, relatively little is known about how these deficits affect neuronal function or how they may be linked to specific RTT endophenotypes. To approach these issues we analyzed synaptic function in the brainstem nucleus tractus solitarius (nTS), the principal site for integration of primary visceral afferent inputs to central autonomic pathways and a region in which we found markedly reduced levels of BDNF in Mecp2 mutants. Our results demonstrate that the amplitude of spontaneous miniature and evoked EPSCs in nTS neurons is significantly increased in Mecp2 null mice and, accordingly, that mutant cells are more likely than wildtype to fire action potentials in response to primary afferent stimulation. These changes occur without any increase in intrinsic neuronal excitability and are unaffected by blockade of inhibitory GABA currents. However, this synaptopathy is associated with decreased BDNF availability in the primary afferent pathway and can be rescued by application of exogenous BDNF. On the basis of these findings we hypothesize that altered sensory gating in nTS contributes to cardiorespiratory instability in RTT and that nTS is a site at which restoration of normal BDNF signaling could help reestablish normal homeostatic controls.

Synaptic Dysfunction in Neurodevelopmental Disorders Associated with Autism and Intellectual Disabilities

“…These findings show that the synaptic abnormalities seen in the RTT model are partially reversible using this pharmacological approach. Kline et al (2010) evaluated the synaptic function of the nucleus tractus solitarius of Mecp2-null mice and found that the mEPSCs are reduced in these mice. Because this synaptic dysfunction was accompanied by decreased BDNF, they applied exogenous BDNF to the brain stem preparation and found that it rescued the synaptic defects (Kline et al 2010).…”

“…Kline et al (2010) evaluated the synaptic function of the nucleus tractus solitarius of Mecp2-null mice and found that the mEPSCs are reduced in these mice. Because this synaptic dysfunction was accompanied by decreased BDNF, they applied exogenous BDNF to the brain stem preparation and found that it rescued the synaptic defects (Kline et al 2010). Another pathway that is altered in RTT is the AKT/mTOR signaling pathway, which is decreased before symptom onset as evidenced by significant reductions in levels of phosphorylated ribosomal protein S6 (rpS6) in neurons of Mecp2-null mice (Ricciardi et al 2011).…”

“…The reductions of BDNF levels in Mecp2-null mice coupled with the amelioration of phenotypes when BDNF is used exogenously or genetically (Chang et al 2006;Kline et al 2010) raise the possibility that drugs that enhance BDNF signaling might rescue RTT phenotypes. The vast number of gene expression changes are sure to contribute to the various RTT phenotypes; thus, therapies targeting chromatin-remodeling proteins such as histone deacetylase or histone acetylase might prove useful.…”

Tissue plasminogen activator regulates Purkinje neuron development and survival

“…Levels of BDNF and TrkB in developing brains vary under different physiological and pathological conditions (43,44). We find that granule cells are the predominant producers of BDNF, a ligand, whereas PNs are rich in its receptor, TrkB.…”

A review of Rett syndrome (RTT) with induced pluripotent stem cells

“…Treatment with insulin growth factor 1, a growth factor known to ameliorate the phenotype of RTT mice, improved the RTT iPSCneuronal phenotypes, providing evidence that synaptic defects can be rescued in neurons derived from RTT patients (14,32,146). The importance of the PI3K pathway is reflected in a number of therapies designed for RTT that aim to restore its activity through the direct application or augmented endogenous synthesis of growth factors such as BDNF or IGF-1 (146)(147)(148)(149). These therapies target the tyrosine kinase receptors and hyper-activation of their subsequent downstream cascade that will cause increased protein synthesis in the end impact synaptic maturation and function (73).…”