Synaptic dysfunction of Aldh1a1 neurons in the ventral tegmental area causes impulsive behaviors.
Synaptic dysfunction of Aldh1a1 neurons in the ventral tegmental area causes impulsive behaviors.
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腹侧被盖区 Aldh1a1 神经元的突触功能障碍会导致冲动行为。
DOI：
10.1186/s13024-021-00494-9
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发表时间：
2021-10-26
影响因子：
15.1
通讯作者：
Lu Y
中科院分区：
文献类型：
--
作者：
Li X;Chen W;Huang X;Jing W;Zhang T;Yu Q;Yu H;Li H;Tian Q;Ding Y;Lu Y
Aldh 1a 1神经元是γ-氨基丁酸（GABA）抑制性神经元的一种亚型，其使用Aldh 1a 1而不是谷氨酸脱羧酶（GAD）作为合成GABA递质的酶。然而，这种新发现的抑制性中间神经元亚型的行为和回路仍然未知。我们产生了一个突变的小鼠系，其中环化重组酶（CRE）的Aldh 1a 1启动子的控制下表达（Aldh 1a 1-CRE小鼠）。使用这种突变株的小鼠与杂合子雄性阿尔茨海默病（AD）相关模型小鼠（APPswe/PSEN 1dE 9，或AD小鼠）和遗传修饰的逆行和顺行突触追踪策略，我们研究了一个特定的突触回路的Aldh 1a 1神经元与系统水平的功能和疾病的进展在AD小鼠。我们证明，Aldh 1a 1神经元编码延迟的满足，测量自我控制技能的决策投射抑制性突触直接到兴奋性谷氨酸神经元在中间外侧隔（EGNIS）和接受突触输入层5 b锥体神经元在内侧前额叶皮层（L5 PN）。L5 PN → Aldh 1a 1突触传递经历长时程增强（LTP）。通过遗传沉默突触前终末或拮抗突触后受体的通路特异性抑制损害延迟满足，导致冲动行为。进一步的研究表明，外源性Aldh 1a 1（eAldh 1a 1）基因的表达可以重建Aldh 1a 1缺陷神经元，恢复Aldh 1a 1 → EGNIS突触传递，挽救AD小鼠的冲动行为。这些结果不仅确定了一个特定的功能和电路的Aldh 1a 1神经元，但也提供了一个重要的，但研究不足的突触机制，在AD的早期阶段的冲动行为的诱导细胞的入口点。在线版本包含补充材料，可通过10.1186/s13024-021-00494-9获得。
Aldh1a1 neurons are a subtype of gamma-aminobutyric acid (GABA) inhibitory neurons that use Aldh1a1 rather than glutamate decarboxylase (GAD) as an enzyme for synthesizing GABA transmitters. However, the behaviors and circuits of this newly identified subtype of inhibitory interneurons remain unknown. We generated a mutant mouse line in which cyclization recombination enzyme (CRE) was expressed under the control of the Aldh1a1 promotor (Aldh1a1-CRE mice). Using this mutant strain of mice together with the heterozygous male Alzheimer’s disease (AD) related model mice (APPswe/PSEN1dE9, or AD mice) and a genetically modified retrograde and anterograde synaptic tracing strategy, we have studied a specific synaptic circuit of Aldh1a1 neurons with system-level function and disease progression in AD mice. We demonstrate that Aldh1a1 neurons encode delay of gratification that measures self-control skills in decision making by projecting inhibitory synapses directly onto excitatory glutamate neurons in the intermediate lateral septum (EGNIS) and receiving synaptic inputs from layer 5b pyramidal neurons in the medial prefrontal cortex (L5PN). L5PN → Aldh1a1 synaptic transmission undergoes long-term potentiation (LTP). Pathway specific inhibition by either genetic silencing presynaptic terminals or antagonizing postsynaptic receptors impairs delay of gratification, resulting in the impulsive behaviors. Further studies show that reconstitution of Aldh1a1-deficient neurons with the expression of exogenous Aldh1a1 (eAldh1a1) restores Aldh1a1 → EGNIS synaptic transmission and rescues the impulsive behaviors in AD mice. These results not only identify a specific function and circuit of Aldh1a1 neurons but also provide a cellular point of entry to an important but understudied synaptic mechanism for the induction of impulsive behaviors at an early stage of AD. The online version contains supplementary material available at 10.1186/s13024-021-00494-9.
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影响因子：
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