Montréal Neurological Institute, Department of Neurology & Neurosurgery, McGill University, 3801 Rue University, Montréal, Québec, H3A 2B4, Canada.
NSERC CREATE Neuroengineering Training Program, McGill University, Montréal, Canada.
Mol Brain. 2020 Apr 7;13(1):56. doi: 10.1186/s13041-020-00597-2.
The receptor deleted in colorectal cancer (DCC) and its ligand netrin-1 are essential for axon guidance during development and are expressed by neurons in the mature brain. Netrin-1 recruits GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and is critical for long-term potentiation (LTP) at CA3-CA1 hippocampal Schaffer collateral synapses, while conditional DCC deletion from glutamatergic neurons impairs hippocampal-dependent spatial memory and severely disrupts LTP induction. DCC co-fractionates with the detergent-resistant component of postsynaptic density, yet is enriched in axonal growth cones that differentiate into presynaptic terminals during development. Specific presynaptic and postsynaptic contributions of DCC to the function of mature neural circuits have yet to be identified. Employing hippocampal subregion-specific conditional deletion of DCC, we show that DCC loss from CA1 hippocampal pyramidal neurons resulted in deficits in spatial memory, increased resting membrane potential, abnormal dendritic spine morphology, weaker spontaneous excitatory postsynaptic activity, and reduced levels of postsynaptic adaptor and signaling proteins; however, the capacity to induce LTP remained intact. In contrast, deletion of DCC from CA3 neurons did not induce detectable changes in the intrinsic electrophysiological properties of CA1 pyramidal neurons, but impaired performance on the novel object place recognition task as well as compromised excitatory synaptic transmission and LTP at Schaffer collateral synapses. Together, these findings reveal specific pre- and post-synaptic contributions of DCC to hippocampal synaptic plasticity underlying spatial memory.
结直肠癌缺失受体（DCC）及其配体轴突导向因子 1（netrin-1）在发育过程中对轴突导向至关重要，并且在成熟大脑的神经元中表达。netrin-1 募集包含 GluA1 的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR），对于 CA3-CA1 海马沙尔夫侧枝突触的长时程增强（LTP）至关重要，而条件性 DCC 从谷氨酸能神经元中的缺失会损害海马依赖的空间记忆，并严重破坏 LTP 的诱导。DCC 与突触后密度的去污剂抗性成分共分离，但在发育过程中分化为突触前末端的轴突生长锥中丰富。DCC 对成熟神经回路功能的特定突触前和突触后贡献尚未确定。通过海马亚区特异性条件性 DCC 删除，我们表明 CA1 海马锥体神经元中 DCC 的缺失导致空间记忆缺陷、静息膜电位升高、树突棘形态异常、自发性兴奋性突触后活动减弱以及突触后衔接蛋白和信号蛋白水平降低；然而，诱导 LTP 的能力仍然完好。相比之下，从 CA3 神经元中删除 DCC 不会引起 CA1 锥体神经元内在电生理特性的可检测变化，但会损害新颖物体位置识别任务的表现，并损害 Schaffer 侧枝突触的兴奋性突触传递和 LTP。总之，这些发现揭示了 DCC 对空间记忆相关海马突触可塑性的特定突触前和突触后贡献。
