Department of Psychology, The Hebrew University of Jerusalem, Jerusalem, Israel.
Brain Behav Immun. 2011 Jul;25(5):1008-16. doi: 10.1016/j.bbi.2010.11.007. Epub 2010 Nov 17.
Recent studies indicate that astrocytes play an integral role in neural and synaptic functioning. To examine the implications of these findings for neurobehavioral plasticity we investigated the involvement of astrocytes in memory and long-term potentiation (LTP), using a mouse model of impaired learning and synaptic plasticity caused by genetic deletion of the interleukin-1 receptor type I (IL-1RI). Neural precursor cells (NPCs), derived from either wild type (WT) or IL-1 receptor knockout (IL-1rKO) neonatal mice, were labeled with bromodeoxyuridine (BrdU) and transplanted into the hippocampus of either IL-1rKO or WT adult host mice. Transplanted NPCs survived and differentiated into astrocytes (expressing GFAP and S100β), but not to neurons or oligodendrocytes. The NPCs-derived astrocytes from WT but not IL-1rKO mice displayed co-localization of GFAP with the IL-1RI. Four to twelve weeks post-transplantation, memory functioning was examined in the fear-conditioning and the water maze paradigms and LTP of perforant path-dentate gyrus synapses was assessed in anesthetized mice. As expected, IL-1rKO mice transplanted with IL-1rKO cells or sham operated displayed severe memory disturbances in both paradigms as well as a marked impairment in LTP. In contrast, IL-1rKO mice transplanted with WT NPCs displayed a complete rescue of the impaired memory functioning as well as partial restoration of LTP. These findings indicate that astrocytes play a critical role in memory functioning and LTP, and specifically implicate astrocytic IL-1 signaling in these processes. The results suggest novel conceptualization and therapeutic targets for neuropsychiatric disorders characterized by impaired astrocytic functioning concomitantly with disturbed memory and synaptic plasticity.
最近的研究表明，星形胶质细胞在神经和突触功能中起着不可或缺的作用。为了研究这些发现对神经行为可塑性的影响，我们使用白细胞介素-1 受体 I 型（IL-1RI）基因缺失导致学习和突触可塑性受损的小鼠模型，研究了星形胶质细胞在记忆和长时程增强（LTP）中的作用。神经前体细胞（NPCs）来源于野生型（WT）或白细胞介素-1 受体敲除（IL-1rKO）新生小鼠，用溴脱氧尿苷（BrdU）标记，并移植到 IL-1rKO 或 WT 成年宿主小鼠的海马体中。移植的 NPCs 存活并分化为星形胶质细胞（表达 GFAP 和 S100β），但不能分化为神经元或少突胶质细胞。来自 WT 但不是 IL-1rKO 小鼠的 NPC 衍生星形胶质细胞显示 GFAP 与 IL-1RI 共定位。移植后 4 至 12 周，在恐惧条件反射和水迷宫范式中检查记忆功能，并在麻醉小鼠中评估穿通路径-齿状回突触的 LTP。正如预期的那样，移植了 IL-1rKO 细胞或假手术的 IL-1rKO 小鼠在两种范式中都表现出严重的记忆障碍，以及 LTP 的明显损害。相比之下，移植了 WT NPC 的 IL-1rKO 小鼠表现出受损记忆功能的完全恢复以及 LTP 的部分恢复。这些发现表明星形胶质细胞在记忆功能和 LTP 中起着关键作用，并且特别表明星形胶质细胞的 IL-1 信号在这些过程中起作用。这些结果为伴有记忆和突触可塑性障碍的神经精神疾病提供了新的概念化和治疗靶点。
