Deletion of BDNF in Pax2 Lineage-Derived Interneuron Precursors in the Hindbrain Hampers the Proportion of Excitation/Inhibition, Learning, and Behavior.
Deletion of BDNF in Pax2 Lineage-Derived Interneuron Precursors in the Hindbrain Hampers the Proportion of Excitation/Inhibition, Learning, and Behavior.
复制标题
DOI：
10.3389/fnmol.2021.642679
复制
发表时间：
2021
影响因子：
4.8
通讯作者：
Knipper M
中科院分区：
文献类型：
--
作者：
Eckert P;Marchetta P;Manthey MK;Walter MH;Jovanovic S;Savitska D;Singer W;Jacob MH;Rüttiger L;Schimmang T;Milenkovic I;Pilz PKD;Knipper M
许多研究表明，特定GABA能前体细胞从腭下到皮质的适当整合或迁移的缺陷可导致与智力残疾相关的严重认知功能障碍和神经发育发病机制。一组不同的表达Pax 2的GABA能前体细胞迁移到后脑区域，靶向例如听觉或躯体感觉脑干区域。我们证明了在BdnfPax 2KO的Pax 2谱系后代中BDNF的缺失会导致严重的认知障碍。在BdnfPax 2KO中，在听觉皮层（AC）和海马区发现了正常数量的小清蛋白阳性中间神经元（PV-IN），这与神经元结构域中的PV标记减少和这些相同区域中锥体神经元中活性调节的细胞因子相关蛋白（Arc/Arg3.1;此处：Arc）水平升高密切相关。这种AC和海马的抑制/兴奋平衡的不成熟伴随着LTP升高、LTP/LTD调节降低（声音诱导的）、学习受损、焦虑升高和社会行为缺陷，总体上代表了自闭症样表型。在耳蜗背核（DCN）脑干神经元中，在其他接近正常听力的BdnfPax 2KO中，强直性抑制强度降低和自发放电率升高表明，细粒度神经元特异性脑干活动减少阻碍了功能（海马）回路中AC抑制网络的活动驱动整合。这导致在LTP/LTD可塑性期间无法缩放海马后突触。因此，脑下部区域Pax 2谱系后代中的BDNF应该被认为是促进大脑疾病（包括自闭症）发展的新候选者。
Numerous studies indicate that deficits in the proper integration or migration of specific GABAergic precursor cells from the subpallium to the cortex can lead to severe cognitive dysfunctions and neurodevelopmental pathogenesis linked to intellectual disabilities. A different set of GABAergic precursors cells that express Pax2 migrate to hindbrain regions, targeting, for example auditory or somatosensory brainstem regions. We demonstrate that the absence of BDNF in Pax2-lineage descendants of BdnfPax2KOs causes severe cognitive disabilities. In BdnfPax2KOs, a normal number of parvalbumin-positive interneurons (PV-INs) was found in the auditory cortex (AC) and hippocampal regions, which went hand in hand with reduced PV-labeling in neuropil domains and elevated activity-regulated cytoskeleton-associated protein (Arc/Arg3.1; here: Arc) levels in pyramidal neurons in these same regions. This immaturity in the inhibitory/excitatory balance of the AC and hippocampus was accompanied by elevated LTP, reduced (sound-induced) LTP/LTD adjustment, impaired learning, elevated anxiety, and deficits in social behavior, overall representing an autistic-like phenotype. Reduced tonic inhibitory strength and elevated spontaneous firing rates in dorsal cochlear nucleus (DCN) brainstem neurons in otherwise nearly normal hearing BdnfPax2KOs suggests that diminished fine-grained auditory-specific brainstem activity has hampered activity-driven integration of inhibitory networks of the AC in functional (hippocampal) circuits. This leads to an inability to scale hippocampal post-synapses during LTP/LTD plasticity. BDNF in Pax2-lineage descendants in lower brain regions should thus be considered as a novel candidate for contributing to the development of brain disorders, including autism.
登录
查看更多内容
影响因子：
3.1
作者：
Bakos J;Zatkova M;Bacova Z;Ostatnikova D
通讯作者：
Ostatnikova D
影响因子：
11
作者：
Canetta S;Bolkan S;Padilla-Coreano N;Song LJ;Sahn R;Harrison NL;Gordon JA;Brown A;Kellendonk C
通讯作者：
Kellendonk C
影响因子：
6.2
作者：
Das, Ishita;Estevez, Marcel A.;Banerjee-Basu, Sharmila
通讯作者：
Banerjee-Basu, Sharmila
影响因子：
2.8
作者：
Felix RA 2nd;Elde CJ;Nevue AA;Portfors CV
通讯作者：
Portfors CV
影响因子：
3.4
作者：
Blair, Laura J.;Criado-Marrero, Marangelie;Dickey, Chad A.
通讯作者：
Dickey, Chad A.