Abstract
Brain-derived neurotrophic factor (Bdnf) has been implicated in several neurological disorders including Rett syndrome (RTT), an X-linked neurodevelopmental disorder caused by loss-of-function mutations in the transcriptional modulator methyl-CpG-binding protein 2 (MECP2). The human BDNF gene has a single nucleotide polymorphism (SNP)—a methionine (met) substitution for valine (val) at codon 66—that affects BDNF’s trafficking and activity-dependent release and results in cognitive dysfunction. Humans that are carriers of the met-BDNF allele have subclinical memory deficits and reduced hippocampal volume and activation. It is still unclear whether this BDNF SNP affects the clinical outcome of RTT individuals. To evaluate whether this BDNF SNP contributes to RTT pathophysiology, we examined the consequences of expression of either val-BDNF or met-BDNF on dendrite and dendritic spine morphology, and synaptic function in cultured hippocampal neurons from wildtype (WT) and Mecp2 knockout (KO) mice. Our findings revealed that met-BDNF does not increase dendritic growth and branching, dendritic spine density and individual spine volume, and the number of excitatory synapses in WT neurons, as val-BDNF does. Furthermore, met-BDNF reduces dendritic complexity, dendritic spine volume and quantal excitatory synaptic transmission in Mecp2 KO neurons. These results suggest that the val-BDNF variant contributes to RTT pathophysiology, and that BDNF-based therapies should take into consideration the BDNF genotype of the RTT individuals.
Highlights
Brain-derived neurotrophic factor (Bdnf ) has been implicated in several neurological disorders due to its widespread function in neuronal development, plasticity, differentiation and survival (Poo, 2001; Fahnestock et al, 2002; Gines et al, 2010; Hartmann et al, 2012)
Met-BDNF-expressing neurons showed a larger fraction of soma and a smaller fraction of dendrites filled with BDNF-GFP compared to val-BDNF-expressing neurons (Figure 1C; val-BDNF soma = 21.02 ± 2.68%; met-BDNF soma = 33.91 ± 3.72%; p = 0.0049)
Such restricted distribution of BDNF-GFP was observed in met-BDNF-expressing hippocampal neurons from Mecp2 KO mice (Figures 1D–F; GFP = 1766 ± 175.4 μm, n = 10 neurons; val-BDNF = 1483 ± 135.6 μm, n = 20; p = 0.1130 GFP vs. val; met-BDNF = 952 ± 98.6 μm, n = 17; p = 0.0021 val vs. met; val-BDNF soma = 21.27 ± 1.73%; met-BDNF soma = 30.68 ± 2.88%; p = 0.0032)
Summary
Brain-derived neurotrophic factor (Bdnf ) has been implicated in several neurological disorders due to its widespread function in neuronal development, plasticity, differentiation and survival (Poo, 2001; Fahnestock et al, 2002; Gines et al, 2010; Hartmann et al, 2012). The human BDNF gene has a SNP—a methionine (met) substitution for valine (val) at codon 66—that affects BDNF trafficking and activity-dependent release (Egan et al, 2003). This SNP is associated with a variety of neuropsychiatric disorders and cognitive dysfunction (Momose et al, 2002; Neves-Pereira et al, 2002; Ventriglia et al, 2002; Egan et al, 2003; Sen et al, 2003; Lu et al, 2013). Several studies have reported that humans and rodents carrying the met BDNF allele display smaller hippocampal volumes and exhibit profound deficits in hippocampal-dependent memory tasks, suggestive of reduced neuroplasticity (Egan et al, 2003; Hariri et al, 2003; Pezawas et al, 2004; Szeszko et al, 2005; Chen et al, 2006; Ninan et al, 2010; Bath et al, 2012; Baj et al, 2013)
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