Neurobiology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, 111 TW Alexander Dr., Research Triangle Park, NC, 27709, USA.
Neurobiology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, 111 TW Alexander Dr., Research Triangle Park, NC, 27709, USA.
Neuropharmacology. 2021 Jun 15;191:108589. doi: 10.1016/j.neuropharm.2021.108589. Epub 2021 Apr 30.
The medial septum/diagonal band of Broca (MS/DBB) receives direct GABAergic input from the hippocampus via hippocamposeptal (HS) projection neurons as part of a reciprocal loop that mediates cognition and is altered in Alzheimer's disease. Cholinergic and GABAergic interactions occur throughout the MS/DBB, but it is not known how HS GABA release is impacted by these circuits. Most HS neurons contain somatostatin (SST), so to evoke HS GABA release we expressed Cre-dependent mCherry/channelrhodopisin-2 (ChR2) in the hippocampi of SST-IRES-Cre mice and then used optogenetics to stimulate HS fibers while performing whole-cell patch clamp recordings from MS/DBB neurons in acute slices. We found that the acetylcholine receptor (AChR) agonist carbachol and the GABA receptor (GABAR) agonist baclofen significantly decreased HS GABA release in the MS/DBB. Carbachol's effects were blocked by eliminating local GABAergic activity or inhibiting GABARs, indicating that it was indirectly decreasing HS GABA release by increasing GABAergic tone. There was no effect of acute exposure to amyloid-β on HS GABA release. Repetitive stimulation of HS fibers increased spontaneous GABA release in the MS/DBB, revealing that HS projections can modulate local GABAergic tone. These results show that HS GABA release has far-reaching impacts on overall levels of inhibition in the MS/DBB and is under regulatory control by cholinergic and GABAergic activity. This bidirectional modulation of GABA release from local and HS projections in the MS/DBB will likely have profound impact not only on activity within the MS/DBB, but also on output to the hippocampus and hippocampal-dependent learning and memory.
内侧隔核/布罗卡斜带（MS/DBB）通过海马伞（HS）投射神经元接收来自海马的直接 GABA 能输入，作为介导认知的互惠环路的一部分，并且在阿尔茨海默病中发生改变。胆碱能和 GABA 能相互作用发生在整个 MS/DBB 中，但尚不清楚这些回路如何影响 HS GABA 的释放。大多数 HS 神经元含有生长抑素（SST），因此为了引发 HS GABA 的释放，我们在 SST-IRES-Cre 小鼠的海马中表达了 Cre 依赖性 mCherry/通道视紫红蛋白-2（ChR2），然后使用光遗传学刺激 HS 纤维，同时在急性切片中进行 MS/DBB 神经元的全细胞膜片钳记录。我们发现，乙酰胆碱受体（AChR）激动剂卡巴胆碱和 GABA 受体（GABAR）激动剂巴氯芬显著降低了 MS/DBB 中的 HS GABA 释放。卡巴胆碱的作用被消除局部 GABA 能活性或抑制 GABAR 所阻断，表明它通过增加 GABA 能张力间接降低 HS GABA 的释放。急性暴露于淀粉样β对 HS GABA 的释放没有影响。HS 纤维的重复刺激增加了 MS/DBB 中的自发性 GABA 释放，表明 HS 投射可以调节局部 GABA 能张力。这些结果表明，HS GABA 的释放对 MS/DBB 中整体抑制水平具有深远影响，并且受到胆碱能和 GABA 能活动的调节控制。MS/DBB 中局部和 HS 投射的 GABA 释放的这种双向调制不仅可能对 MS/DBB 内的活动产生深远影响，而且对向海马的输出以及海马依赖性学习和记忆也有深远影响。
