RESUMO
BACKGROUND: Activity-dependent competition that operates on branch stability or formation plays a critical role in shaping the pattern and complexity of axonal terminal arbors. In the mammalian central nervous system (CNS), the effect of activity-dependent competition on axon arborization and on the assembly of sensory maps is well established. However, the molecular pathways that modulate axonal-branch stability or formation in competitive environments remain unknown. RESULTS: We establish an in vivo axonal-competition paradigm in the mouse olfactory system by employing a genetic strategy that permits suppression of neurosecretory activity in random subsets of olfactory sensory neurons (OSNs). Long-term follow up confirmed that this genetic manipulation triggers competition by revealing a bias toward selective stabilization of active arbors and local degeneration of synaptically silent ones. By using a battery of genetically modified mouse models, we demonstrate that a decrease either in the total levels or the levels of activity-dependent secreted BDNF (due to a val66met substitution), rescues silent arbors from withering. We show that this effect may be mediated, at least in part, by p75(NTR). CONCLUSIONS: We establish and experimentally validate a genetic in vivo axonal-competition paradigm in the mammalian CNS. By using this paradigm, we provide evidence for a specific effect of BDNF signaling on terminal-arbor pruning under competition in vivo. Our results have implications for the formation and refinement of the olfactory and other sensory maps, as well as for neuropsychiatric diseases and traits modulated by the BDNF val66met variant.
Assuntos
Axônios/fisiologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Transdução de Sinais/genética , Substituição de Aminoácidos , Animais , Fator Neurotrófico Derivado do Encéfalo/química , Fator Neurotrófico Derivado do Encéfalo/genética , Camundongos , Camundongos Transgênicos , Neurônios Aferentes/fisiologia , Receptor de Fator de Crescimento Neural/metabolismo , Receptor de Fator de Crescimento Neural/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Olfato/genética , Olfato/fisiologiaRESUMO
Individuals with 22q11.2 microdeletions have cognitive deficits and a high risk of developing schizophrenia. Here we provide evidence that primary hippocampal neurons from a mouse model of 22q11.2 deletion (Df(16)A(+/-) mice) have decreased density of dendritic spines and glutamatergic synapses, as well as impaired dendritic growth. These deficits were prevented by introduction of the enzymatically active ZDHHC8 palmitoyltransferase encoded by a gene in the 22q11.2 locus, and they were also observed in primary cultures from Zdhhc8-deficient mice. Many of these deficits were also present in the hippocampi of adult Df(16)A(+/-) and Zdhhc8-deficient mice. Finally, we provide evidence that PSD95 is one of the substrates of ZDHHC8. Our analysis reveals that 22q11.2 microdeletion results in deficits in neuronal development and suggests that impaired neuronal protein palmitoylation contributes to many of these deficits.
Assuntos
Aciltransferases/genética , Encefalopatias/patologia , Aberrações Cromossômicas , Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Neurônios/patologia , Aciltransferases/química , Animais , Células Cultivadas , Dendritos/patologia , Espinhas Dendríticas/patologia , Diagnóstico por Imagem/métodos , Modelos Animais de Doenças , Proteína 4 Homóloga a Disks-Large , Embrião de Mamíferos , Ácido Glutâmico/metabolismo , Proteínas de Fluorescência Verde/biossíntese , Guanilato Quinases , Hipocampo/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Potenciais da Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Neurônios/fisiologia , Sinapses/genética , Sinapses/patologia , Sinapses/fisiologia , Transfecção/métodosRESUMO
We evaluated a possible association between the brain-derived neurotrophic factor (BDNF) gene and susceptibility to obsessive-compulsive disorder (OCD) by genotyping a number of single-nucleotide polymorphisms (SNPs) and one microsatellite marker from the extended BDNF locus in 164 triads with OCD. Extensive background linkage disequilibrium was observed at this locus. Single-locus transmission-distortion tests revealed significant evidence of association with the disease for all the BDNF gene markers tested, including a Val66Met variation affecting the sequence of the proBDNF protein. Analysis of multi-SNP haplotypes provided similar results. Haplotype transmission comparisons in this and previous studies point to a functionally distinct BDNF haplotype uniquely marked by the rare Met66 allele, which is undertransmitted and likely confers a protective effect in OCD and other psychiatric disorders.