Rett syndrome (RTT), an autism spectrum disorder, is a devastating childhood disorder due to its impact on individuals (1:10,000-15,000 births worldwide), their families and society. RTT is caused by loss-of- function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2), a transcriptional regulator that binds to methylated CpG sites in promoter regions of DNA. An imbalance of excitatory and inhibitory synaptic function in the hippocampus has been implicated in neurodevelopmental disorders associated with cognitive impairments and mental retardation. Mouse cortical neurons lacking Mecp2 show low levels of neuronal activity caused by an excitation/inhibition imbalance that favors synaptic inhibition, and Mecp2 expression levels modulate excitatory synapse formation between hippocampal neurons. One of the target genes of Mecp2 transcriptional control is Brain-derived neurotrophic factor (Bdnf), a potent modulator of activity-dependent synaptic development, function and plasticity. Considering that BDNF is critical for the maturation of inhibitory GABAergic synapses, and based on our Preliminary Results, our general hypothesis is that impaired development of inhibitory GABAergic synapses due to reduced activity- dependent BDNF release from Mecp2-deficient neurons causes an imbalance of excitatory and inhibitory synaptic function in the hippocampus. We propose the following four Specific Aims: (1) test if the hyperexcitable hippocampal network of neuronal Mecp2 null mice is caused by impaired GABAergic synapse function in area CA3;(2) test whether activity-dependent BDNF release from mossy fibers, the axons of dentate gyrus granule cells, is reduced in neuronal Mecp2 null mice;(3) generate a novel RTT model - dentate granule cell-specific Mecp2 knockout mice - and test whether hippocampal hyperexcitability is associated with impaired activity-dependent BDNF release from granule cell mossy fibers;(4) test if enhancing BDNF expression or mimicking BDNF/TrkB signaling prevents hippocampal hyperexcitability in Mecp2 null mice and dentate granule cell-specific Mecp2 knockout mice. We anticipate that the proposed experiments will yield novel information regarding the consequences of Mecp2 deletion for the excitation/inhibition balance in the hippocampus, uncovering fundamental brain mechanisms involved in the neuropathology of RTT and Autism Spectrum Disorders, and testing an experimental rationale to relieve cognitive impairments and mental retardation in children with associated neurodevelopmental disorders.
Rett syndrome (RTT) is an X-linked neurodevelopmental disorder associated with autism and mental retardation, which is caused by mutations in MECP2, a DNA-binding protein that regulates target genes, including Bdnf. We will test whether impaired development of hippocampal inhibitory synapses due to reduced BDNF release contributes to the excitatory/inhibitory imbalance of synaptic function implicated in cognitive impairments and autism in RTT.
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|Xu, Xin; Kozikowski, Alan P; Pozzo-Miller, Lucas (2014) A selective histone deacetylase-6 inhibitor improves BDNF trafficking in hippocampal neurons from Mecp2 knockout mice: implications for Rett syndrome. Front Cell Neurosci 8:68|
|Li, Wei; Pozzo-Miller, Lucas (2014) BDNF deregulation in Rett syndrome. Neuropharmacology 76 Pt C:737-46|
|Larimore, Jennifer; Ryder, Pearl V; Kim, Kun-Yong et al. (2013) MeCP2 regulates the synaptic expression of a Dysbindin-BLOC-1 network component in mouse brain and human induced pluripotent stem cell-derived neurons. PLoS One 8:e65069|
|Xu, Xin; Pozzo-Miller, Lucas (2013) A novel DNA-binding feature of MeCP2 contributes to Rett syndrome. Front Cell Neurosci 7:64|
|Chapleau, Christopher A; Lane, Jane; Larimore, Jennifer et al. (2013) Recent Progress in Rett Syndrome and MeCP2 Dysfunction: Assessment of Potential Treatment Options. Future Neurol 8:|
|Chapleau, Christopher A; Lane, Jane; Pozzo-Miller, Lucas et al. (2013) Evaluation of current pharmacological treatment options in the management of Rett syndrome: from the present to future therapeutic alternatives. Curr Clin Pharmacol 8:358-69|
|Chapleau, Christopher A; Pozzo-Miller, Lucas (2012) Divergent roles of p75NTR and Trk receptors in BDNF's effects on dendritic spine density and morphology. Neural Plast 2012:578057|
|Calfa, Gaston; Percy, Alan K; Pozzo-Miller, Lucas (2011) Experimental models of Rett syndrome based on Mecp2 dysfunction. Exp Biol Med (Maywood) 236:3-19|
|Calfa, Gaston; Hablitz, John J; Pozzo-Miller, Lucas (2011) Network hyperexcitability in hippocampal slices from Mecp2 mutant mice revealed by voltage-sensitive dye imaging. J Neurophysiol 105:1768-84|
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