Postnatal Growth Defects in Mice with Constitutive Depletion of Central Serotonin
Postnatal Growth Defects in Mice with Constitutive Depletion of Central Serotonin
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DOI：
10.1021/cn300165x
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发表时间：
2013-01-01
影响因子：
5
通讯作者：
Gaspar, Patricia
中科院分区：
文献类型：
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作者：
Narboux-Neme, Nicolas;Angenard, Gaelle;Gaspar, Patricia
尽管5-羟色胺(5-羟色胺)的营养作用已被证实，但只有极少的发育缺陷被报道在结构性低血压的小鼠品系中。我们分析了中枢5-羟色胺水平结构性降低的三个不同突变小鼠品系的出生后生长和皮质发育。我们比较了两个先前发表的5-羟色胺严重(-95%)缺失的小鼠品系，色氨酸羟化酶(TPH)2(-/-)小鼠品系和VMAT2(sert-cre)小鼠，其中VMAT2缺失是由5-HT中缝神经元中的Pet1(VMAT2(pet1-cre))驱动的，导致大脑5-HT水平部分(-75%)降低。我们发现，胚胎正常生长和出生后生长迟缓是所有这些品系小鼠的共同特征。出生后发育迟缓根据脑组织5-羟色胺降低的程度和性别的不同，从轻度到重度不等。VMAT2(SERT-CRE)小鼠通过重建中枢5-羟色胺储备区，恢复了正常生长。生长异常不能与改变食物摄入量或温度控制联系起来。对出生后大脑皮质发育的形态研究表明，VMAT2(sert-cre)和Tph2(-/-)小鼠的皮层上层发育迟缓，而VMAT2(pet1-cre)小鼠则没有。没有发现蛋鸡特异性基因表达的变化，也没有发现桶状皮质发育的形态变化。总体而言，这些观察结果支持了这样的观点，即中枢5-羟色胺信号是小鼠断奶前生长突增所必需的。大脑发育似乎不受严重的中枢性5-羟色胺耗竭的影响，因为它在出生前总体生长，而脑生长减慢和皮质成熟发育延迟发生在出生后。出生后发育过程中发育减少的5-羟色胺信号可能会以影响成人行为的方式调节神经回路的功能和精细结构。
Although the trophic actions of serotonin (5-HT) are well established, only few developmental defects have been reported in mouse strains with constitutive hyposerotonergia. We analyzed postnatal growth and cortical development in three different mutant mouse strains with constitutive reductions in central 5-HT levels. We compared two previously published mouse strains with severe (-95%) depletions of 5-HT, the tryptophan hydroxylase (Tph) 2(-/-) mouse line and VMAT2(sert-cre) mice, with a new strain, in which VMAT2 deletion is driven by Pet1 (VMAT2(pet1-cre)) in 5-HT raphe neurons leading to partial (-75%) reduction in brain 5-HT levels. We find that normal embryonic growth and postnatal growth retardation are common features of all these mouse strains. Postnatal growth retardation varied from mild to severe according to the extent of the brain 5-HT reduction and gender. Normal growth was reinstated in VMAT2(sert-cre) mice by reconstituting central 5-HT stores. Growth abnormalities could not be linked to altered food intake or temperature control. Morphological study of the cerebral cortex over postnatal development showed a delayed maturation of the upper cortical layers in the VMAT2(sert-cre) and Tph2(-/-) mice, but not in the VMAT2(pet1-cre) mice. No changes in layer-specific gene expression or morphological alterations of barrel cortex development were found. Overall, these observations sustain the notion that central 5-HT signaling is required for the preweaning growth spurt of mouse pups. Brain development appeared to be immune to severe central 5-HT depletion for its overall growth during prenatal life, whereas reduced brain growth and delayed cortical maturation development occurred during postnatal life. Reduced developmental 5-HT signaling during postnatal development might modulate the function and fine structure of neural circuits in ways that affect adult behavior.