Functional consequences of in vivo ablation of NG2 cells

描述（由申请人提供）：哺乳动物中枢神经系统含有丰富的、广泛分布的神经胶质祖细胞，称为NG2细胞（也称为少突胶质前体细胞或多突胶质细胞），它们有能力发育成少突胶质细胞，并在损伤和脱髓鞘反应中发生剧烈变化。尽管这些细胞在成人脑和脊髓中保留产生少突胶质细胞的能力，但成人中枢神经系统中的大多数NG2细胞不分化，仍处于“祖细胞”状态。NG2细胞在所有灰质和白质区域以网格状排列，将高度分支的过程延伸到周围的神经细胞，并与神经元形成直接突触，从而提高了它们调节神经元活动和神经回路信息流的可能性。此外，在急性和慢性损伤的反应中，NG2细胞增殖，增加NG2的表达，并促进胶质瘢痕的形成，这表明它们可能有助于限制神经退行性变和促进修复。然而，我们对这些丰富的神经胶质细胞的作用以及它们在缺血性损伤后行为变化的后果的了解非常有限。为了确定NG2细胞在成人大脑中的功能，我们最近开发了转基因小鼠，允许在体内选择性消融NG2细胞。利用这些小鼠，NG2细胞可以从大脑中移除，而不会引起星形胶质细胞或小胶质细胞的反应性变化，也不会导致瘫痪或死亡，这表明这种方法可以用来帮助确定这些无处不在的胶质细胞的功能。在拟议的研究中，我们将选择性地从中枢神经系统中切除NG2细胞，并检查它们的缺失是否会导致神经元活动、突触信号、轴突传导或特定行为方面（如空间记忆、焦虑或感觉运动控制）的改变。此外，我们将研究NG2细胞的去除是否会改变其他胶质细胞对局灶性缺血的反应和神经元损伤的程度。总之，这些探索性研究有可能揭示这种神秘的神经胶质细胞在成人大脑中的新作用，并加深我们对生理和病理条件下神经元和神经胶质细胞之间相互作用的理解。如果NG2细胞参与神经调节和中枢神经系统修复，它们将代表一个额外的治疗靶点，具有减少异常神经元活动、预防慢性疾病的神经退行性变、促进中风后的恢复和修复的潜力。

DESCRIPTION (provided by applicant): The mammalian CNS contains an abundant, widely distributed population of glial progenitors known as NG2 cells (also termed oligodendrocyte precursor cells or polydendrocytes) that have the ability to develop into oligodendrocytes and undergo dramatic changes in response to injury and demyelination. Although these cells retain the capacity to generate oligodendrocytes in the adult brain and spinal cord, most NG2 cells in the adult CNS do not differentiate and remain in a "progenitor" state. NG2 cells are arranged in a grid-like manner in all gray and white matter regions, extend highly ramified processes into the surrounding neuropil, and form direct synapses with neurons, raising the possibility that they modulate the activity of neurons and the flow of information through neural circuits. Moreover, NG2 cells proliferate, increase expression of NG2, and contribute to the formation of glial scars in response to both acute and chronic injury, suggesting that they may help limit neurodegeneration and promote repair. Nevertheless, our knowledge about the roles of these abundant glial cells, and the consequences of their change in behavior following ischemic injury, is very limited. To define the functions of NG2 cells in the adult brain, we recently developed transgenic mice that allow selective ablation of NG2 cells in vivo. Using these mice, NG2 cells can be removed from the brain without inducing reactive changes in astrocytes or microglial cells, or causing paralysis or death, indicating that this approach can be used to help define the functions of these ubiquitous glial cells. In the proposed studies, we will selectively ablate NG2 cells from the CNS in vivo, and examine whether their absence results in alterations in neuronal activity, signaling at synapses, axonal conduction, or specific aspects of behavior, such as spatial memory, anxiety, or sensorimotor control. In addition, we will examine whether removal of NG2 cells alters the response of other glial cells to focal ischemia and the extent of neuronal injury. Together, these exploratory studies have the potential to reveal new roles for this enigmatic population of glial cells in the adult brain, and deepen our understanding of interactions that occur between neurons and glial cells in physiological and pathological conditions. If NG2 cells participate in neuromodulation and CNS repair, they would represent an additional therapeutic target with the potential to reduce abnormal neuronal activity, prevent neurodegeneration in chronic disease, and promote recovery and repair following stroke. PUBLIC HEALTH RELEVANCE: This proposal seeks to determine whether an abundant, widely distributed population of glial cells in adult CNS influences the flow of information through neural circuits and promotes repair following ischemia. These studies have the potential to identify new pathways for regulating abnormal neuronal activity, as well as reducing injury and accelerating recovery after stroke.