Lopez J, Roffwarg H P, Dreher A, Bissette G, Karolewicz B, Shaffery J P
Department of Psychiatry, University of Mississippi School of Medicine, 2500 N State Street, Jackson, MS 39216, USA.
Neuroscience. 2008 Apr 22;153(1):44-53. doi: 10.1016/j.neuroscience.2008.01.072. Epub 2008 Feb 15.
Development of the mammalian CNS requires formation and stabilization of neuronal circuits and synaptic connections. Sensory stimulation provided by the environment orchestrates neuronal circuit formation in the waking state. Endogenous sources of activation are also implicated in these processes. Accordingly we hypothesized that sleep, especially rapid eye movement sleep (REMS), the stage characterized by high neuronal activity that is more prominent in development than adulthood, provides endogenous stimulation, which, like sensory input, helps to stabilize and refine neuronal circuits during CNS development. Young (Y: postnatal day (PN) 16) and adolescent (A: PN44) rats were rapid eye movement sleep-deprived (REMSD) by gentle cage-shaking for only 4 h on 3 consecutive days (total 12 h). The effect of REMS deprivation in Y and A rats was tested 3-7 days after the last deprivation session (Y, PN21-25; A, PN49-53) and was compared with younger (immature, I, PN9-12) untreated, age-matched, treated and normal control groups. REMS deprivation negatively affected the stability of long-term potentiation (LTP) in Y but not A animals. LTP instability in Y-REMSD animals was similar to the instability in even the more immature, untreated animals. Utilizing immunoblots, we identified changes in molecular components of glutamatergic synapses known to participate in mechanisms of synaptic refinement and plasticity. Overall, N-methyl-d-aspartate receptor subunit 2B (NR2B), N-methyl-d-aspartate receptor subunit 2A, AMPA receptor subunit 1 (GluR1), postsynaptic density protein 95 (PSD-95), and calcium/calmodulin kinase II tended to be lower in Y REMSD animals (NR2B, GluR1 and PSD-95 were significantly lower) compared with controls, an effect not present in the A animals. Taken together, these data indicate that early-life REMS deprivation reduces stability of hippocampal neuronal circuits, possibly by hindering expression of mature glutamatergic synaptic components. The findings support a role for REMS in the maturation of hippocampal neuronal circuits.
哺乳动物中枢神经系统（CNS）的发育需要神经元回路和突触连接的形成与稳定。环境提供的感觉刺激在清醒状态下协调神经元回路的形成。内源性激活源也参与这些过程。因此，我们推测睡眠，尤其是快速眼动睡眠（REMS），这个以高神经元活动为特征且在发育过程中比成年期更显著的阶段，提供内源性刺激，就像感觉输入一样，有助于在CNS发育过程中稳定和完善神经元回路。幼年（Y：出生后第16天）和青少年（A：出生后第44天）大鼠通过连续3天每天仅轻柔摇晃笼子4小时（共12小时）来剥夺快速眼动睡眠（REMSD）。在最后一次剥夺实验后3 - 7天（Y，出生后第21 - 25天；A，出生后第49 - 53天）测试Y和A大鼠的REMS剥夺效果，并与更年幼（未成熟，I，出生后第9 - 12天）未处理、年龄匹配的处理组和正常对照组进行比较。REMS剥夺对Y组动物的长时程增强（LTP）稳定性有负面影响，但对A组动物没有影响。Y - REMSD动物的LTP不稳定性甚至与更未成熟的未处理动物相似。利用免疫印迹法，我们确定了已知参与突触细化和可塑性机制的谷氨酸能突触分子成分的变化。总体而言，与对照组相比，Y REMSD动物中的N - 甲基 - D - 天冬氨酸受体亚基2B（NR2B）、N - 甲基 - D - 天冬氨酸受体亚基2A、α - 氨基 - 3 - 羟基 - 5 - 甲基 - 4 - 异恶唑丙酸受体亚基1（GluR1）、突触后致密蛋白95（PSD - 95）和钙/钙调蛋白激酶II往往较低（NR2B、GluR1和PSD - 95显著降低），A组动物中不存在这种效应。综上所述，这些数据表明生命早期的REMS剥夺会降低海马神经元回路的稳定性，可能是通过阻碍成熟谷氨酸能突触成分的表达。这些发现支持了REMS在海马神经元回路成熟中的作用。
