Altered maturation of the primary somatosensory cortex in a mouse model of fragile X syndrome

Abstract

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and results from the loss of the fragile X mental retardation protein (FMRP). Many fragile X-related cognitive and behavioral features emerge during childhood and are associated with abnormal synaptic and cellular organization of the cerebral cortex. Identifying the roles of FMRP in cortical development will provide a basis for understanding the pathogenesis of the syndrome. However, how the loss of FMRP influences the developmental trajectory of cortical maturation remains unclear. We took advantage of the stereotyped and well-characterized development of the murine primary somatosensory cortex to examine cortical maturation during a time-window that corresponds to late embryonic and early postnatal development in the human. In the Fmr1 knockout mouse, we find a delay in somatosensory map formation, alterations in the morphology profile of dendrites and spines of layer 4 neurons and a decrease in the synaptic levels of proteins involved in glutamate receptor signaling at times corresponding to the highest levels of FMRP expression. In contrast, cortical arealization, synaptic density in layer 4 and early postnatal regulation of mRNAs encoding synaptic proteins are not altered in Fmr1 knockout mice. The specificity of the developmental delay in Fmr1 knockout mice indicates that the loss of FMRP does not result in a general stalling of cerebral cortex maturation. Instead, our results suggest that inaccurate timing of developmental processes caused by the loss of FMRP may lead to alterations in neural circuitry that underlie behavioral and cognitive dysfunctions associated with FXS.

Fmr1 deficiency promotes age-dependent alterations in the cortical synaptic proteome

“…Furthermore, we found that neurons derived from KO mice produce many nascent synaptic proteins at a higher rate than that of WT mice, many of which are reportedly direct FMRP targets. Given that FMRP expression declines during later brain maturation (38,39), it may be that the age-dependent differences that we observed between WT and KO synaptic proteomes reflect a declining influence of FMRP (in WT) on nascent protein synthesis at the elongation step.…”

Fragile X mice have robust mGluR5-dependent alterations of social behaviour in the Automated Tube Test

“…Synaptoneurosomes (SNs) were isolated according to Till et al (2012) with minor modifications, one to four weeks after finishing the tube tournaments. Briefly, the frontal parts of freshly isolated cortices were gently homogenized with a Teflon-glass homogenizer (10 mM HEPES, 2 mM EDTA, 2 mM EGTA, 0.5 mM DTT, protease inhibitors (Roche)).…”

Variabilidade do domínio KH-2 da proteína do retardo mental do X frágil (FMRP)

“…Neste estudo, a ausência da FMRP causou defeitos de maturação e proliferação neuronal e dismorfismo de espinhas dendríticas, especificamente no córtex cerebral somatosensorial primário (TILL et al, 2012). Embora a maturação neuronal ainda tenha ocorrido no córtex somatosensorial, sua capacidade de formar circuitos sinápticos foi perdida, o que foi atribuído à redução da plasticidade neuronal.…”

“…Em contraste com nossas observações, Till e colaboradores (TILL et al, 2012) não observaram nenhuma marcação em células da glia. Enquanto a IHQ não permite uma discriminação inequívoca entre células neuronais ou gliais, a maioria das nossas observações ao microscópio em regiões corticais e hipocampais mostrou células com morfologia indicativa de neurônios, enquanto na região do corpo caloso, observamos marcação que é sugestiva de expressão da FMRP e FMRP+12ISO nas fibras de oligodendrócitos (dados não mostrados), que deve ser um achado inespecífico.…”

“…Descreveu-se a expressão da FMRP em células da glia (MIENTJES et al, 2006;PACEY;DOERING, 2007) e que transcritos de origem glial podem ser transportados ativamente para neurônios (GIUDITTA et al, 2008), levantando-se a dúvida sobre a origem dos transcritos que traduzem para a FMRP encontrada em neurônios. Em estudo recente investigou-se a questão, demonstrando-se que a FMRP detectada na região pré-sinaptica é de fato de origem neuronal (AKINS et al, 2012;TILL et al, 2012) e que o aumento da síntese proteica advindo da ausência da FMRP no modelo KO é mais acentuada em áreas com maior densidade neuronal (QIN et al, 2005).…”