RESUMO
Giant ankyrin-B (ankB) is a neurospecific alternatively spliced variant of ANK2, a high-confidence autism spectrum disorder (ASD) gene. We report that a mouse model for human ASD mutation of giant ankB exhibits increased axonal branching in cultured neurons with ectopic CNS axon connectivity, as well as with a transient increase in excitatory synapses during postnatal development. We elucidate a mechanism normally limiting axon branching, whereby giant ankB localizes to periodic axonal plasma membrane domains through L1 cell-adhesion molecule protein, where it couples microtubules to the plasma membrane and prevents microtubule entry into nascent axon branches. Giant ankB mutation or deficiency results in a dominantly inherited impairment in selected communicative and social behaviors combined with superior executive function. Thus, gain of axon branching due to giant ankB-deficiency/mutation is a candidate cellular mechanism to explain aberrant structural connectivity and penetrant behavioral consequences in mice as well as humans bearing ASD-related ANK2 mutations.
Assuntos
Anquirinas/genética , Transtorno do Espectro Autista/genética , Molécula L1 de Adesão de Célula Nervosa/genética , Crescimento Neuronal , Neurônios/metabolismo , Sinapses/metabolismo , Processamento Alternativo , Animais , Anquirinas/metabolismo , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/fisiopatologia , Comportamento Animal , Membrana Celular/metabolismo , Membrana Celular/ultraestrutura , Conectoma , Modelos Animais de Doenças , Função Executiva/fisiologia , Expressão Gênica , Técnicas de Introdução de Genes , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Microtúbulos/metabolismo , Microtúbulos/ultraestrutura , Mutação , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Neurônios/patologia , Cultura Primária de Células , Comportamento Social , Sinapses/patologiaRESUMO
Giant ankyrin-G (gAnkG) coordinates assembly of axon initial segments (AISs), which are sites of action potential generation located in proximal axons of most vertebrate neurons. Here, we identify a mechanism required for normal neural development in humans that ensures ordered recruitment of gAnkG and ß4-spectrin to the AIS. We identified 3 human neurodevelopmental missense mutations located in the neurospecific domain of gAnkG that prevent recruitment of ß4-spectrin, resulting in a lower density and more elongated pattern for gAnkG and its partners than in the mature AIS. We found that these mutations inhibit transition of gAnkG from a closed configuration with close apposition of N- and C-terminal domains to an extended state that is required for binding and recruitment of ß4-spectrin, and normally occurs early in development of the AIS. We further found that the neurospecific domain is highly phosphorylated in mouse brain, and that phosphorylation at 2 sites (S1982 and S2619) is required for the conformational change and for recruitment of ß4-spectrin. Together, these findings resolve a discrete intermediate stage in formation of the AIS that is regulated through phosphorylation of the neurospecific domain of gAnkG.
Assuntos
Anquirinas/genética , Segmento Inicial do Axônio/metabolismo , Citoesqueleto de Actina/metabolismo , Potenciais de Ação/genética , Potenciais de Ação/fisiologia , Animais , Anquirinas/metabolismo , Segmento Inicial do Axônio/fisiologia , Axônios/metabolismo , Células Cultivadas , Células HEK293 , Humanos , Camundongos Knockout , Mutação , Neurônios/metabolismo , Vertebrados/metabolismoRESUMO
The architecture whereby activity across many brain regions integrates to encode individual appetitive social behavior remains unknown. Here we measure electrical activity from eight brain regions as mice engage in a social preference assay. We then use machine learning to discover a network that encodes the extent to which individual mice engage another mouse. This network is organized by theta oscillations leading from prelimbic cortex and amygdala that converge on the ventral tegmental area. Network activity is synchronized with cellular firing, and frequency-specific activation of a circuit within this network increases social behavior. Finally, the network generalizes, on a mouse-by-mouse basis, to encode individual differences in social behavior in healthy animals but fails to encode individual behavior in a 'high confidence' genetic model of autism. Thus, our findings reveal the architecture whereby the brain integrates distributed activity across timescales to encode an appetitive brain state underlying individual differences in social behavior.