通过消除围产期形成的多余突触,在出生后发育过程中可以形成功能成熟的神经回路。在新生啮齿动物的小脑,每个浦肯野细胞(PC)接收来自多个(4个以上)攀爬纤维(CF)的突触输入。在出生后的前3周,来自单个CF的突触输入变得明显更大,而来自其他CF的突触输入在每个PC中被消除,在成年期通过强大的CF导致每个PC的单神经支配。虽然在出生后发育过程中参与CF突触的加强和消除的分子正在被阐明,关于出生后早期CF突触形成的分子机制知之甚少。这里,我们展示了实验证据表明突触组织者,PTPδ,是出生后早期CF突触形成和随后CF到PC突触布线的建立所必需的。我们表明,无论醛缩酶C(Aldoc)的表达如何,从出生后第0天(P0)起,PTPδ位于CF-PC突触处,PC的主要标记,可区分小脑隔室。我们发现,在P12至P29-31的全局PTPδ敲除(KO)小鼠中,主要在不表达Aldoc[Aldoc(-)PC]的PC中,单个强CF沿PC树突的延伸(CF易位)受损。我们还通过形态学和电生理学分析证明,从P3到P13,PTPδKO小鼠中支配单个PC的CF数量少于野生型(WT)小鼠,其中小脑前小叶中CF突触输入的强度显着降低,其中大多数PC是Aldoc(-)。此外,CF特异性PTPδ敲低(KD)导致神经支配PC的CF数量减少,前小叶P10-13处的CF突触输入减少。我们发现成年PTPδKO小鼠的运动性能轻度受损。这些结果表明,PTPδ充当CF-PC形成的突触前组织者,是正常CF-PC突触传递所必需的,CF易位,推测CF突触维持主要在Aldoc(-)PC中。此外,这项研究表明,缺乏PTPδ导致的CF-PC突触形成和发育受损会导致运动性能轻度受损。
Functionally mature neural circuits are shaped during postnatal development by eliminating redundant synapses formed during the perinatal period. In the cerebellum of neonatal rodents, each Purkinje cell (PC) receives synaptic inputs from multiple (more than 4) climbing fibers (CFs). During the first 3 postnatal weeks, synaptic inputs from a single CF become markedly larger and those from the other CFs are eliminated in each PC, leading to mono-innervation of each PC by a strong CF in adulthood. While molecules involved in the strengthening and elimination of CF synapses during postnatal development are being elucidated, much less is known about the molecular mechanisms underlying CF synapse formation during the early postnatal period. Here, we show experimental evidence that suggests that a synapse organizer, PTPδ, is required for early postnatal CF synapse formation and the subsequent establishment of CF to PC synaptic wiring. We showed that PTPδ was localized at CF-PC synapses from postnatal day 0 (P0) irrespective of the expression of Aldolase C (Aldoc), a major marker of PC that distinguishes the cerebellar compartments. We found that the extension of a single strong CF along PC dendrites (CF translocation) was impaired in global PTPδ knockout (KO) mice from P12 to P29-31 predominantly in PCs that did not express Aldoc [Aldoc (-) PCs]. We also demonstrated via morphological and electrophysiological analyses that the number of CFs innervating individual PCs in PTPδ KO mice were fewer than in wild-type (WT) mice from P3 to P13 with a significant decrease in the strength of CF synaptic inputs in cerebellar anterior lobules where most PCs are Aldoc (-). Furthermore, CF-specific PTPδ-knockdown (KD) caused a reduction in the number of CFs innervating PCs with decreased CF synaptic inputs at P10-13 in anterior lobules. We found a mild impairment of motor performance in adult PTPδ KO mice. These results indicate that PTPδ acts as a presynaptic organizer for CF-PC formation and is required for normal CF-PC synaptic transmission, CF translocation, and presumably CF synapse maintenance predominantly in Aldoc (-) PCs. Furthermore, this study suggests that the impaired CF-PC synapse formation and development by the lack of PTPδ causes mild impairment of motor performance.