Traumatic Brain Injury Broadly Affects GABAergic Signaling in Dentate Gyrus Granule Cells
Traumatic Brain Injury Broadly Affects GABAergic Signaling in Dentate Gyrus Granule Cells
复制标题
DOI：
10.1523/eneuro.0055-20.2021
复制
发表时间：
2021-05-01
期刊：
影响因子：
3.4
通讯作者：
Ransom, Christopher B.
中科院分区：
文献类型：
--
作者：
Becerra, Alejandro Parga;Logsdon, Aric F.;Ransom, Christopher B.
创伤性脑损伤（TBI）引起细胞和分子改变，导致神经精神疾病和癫痫。GABA能功能障碍在TBI的病理生理学中占有重要地位，但TBI对海马紧张性抑制的影响仍不确定。我们使用一个严重TBI小鼠模型[控制性皮质撞击（CCI）]来研究齿状回颗粒细胞（DGGCs）中的GABA能信号。基础紧张性GABA电流不受CCI。然而，δ亚基选择性GABA（A）受体激动剂4，5，6，7-四氢异恶唑并[5，4-c]吡啶-3-醇（THIP; 10 μ M）诱导的紧张性电流在CCI同侧的DGGCs（CCI-ipsi）中减少了44%，但在对侧DGGCs中没有减少。THIP电流在损伤后一周明显减少，并持续长达15周。CCI-ipsi细胞中自发IPSC（sIPSC）的频率降低，但sIPSC的振幅和动力学不受影响。免疫组织化学分析显示CCI后GABA（A）受体δ亚基和GABA（B）受体B2亚基的表达分别减少了43%和40%。突触后GABA（B）受体的激活引起紧张性电流的两倍增加，这种作用在CCI-ipsi细胞中明显减弱（减少92%）。在CCI-ipsi细胞中，DGGCs中GABA（B）受体激活的K+电流也显著降低，证实CCI后GABA（B）受体功能缺陷。结果表明CCI后DGGCs中GABA能信号传导广泛中断，相位和紧张性抑制以及GABA（B）受体功能均出现缺陷。预计这些变化会破坏海马网络的运作，并导致严重TBI的后遗症，包括癫痫。
Traumatic brain injury (TBI) causes cellular and molecular alterations that contribute to neuropsychiatric disease and epilepsy. GABAergic dysfunction figures prominently in the pathophysiology of TBI, yet the effects of TBI on tonic inhibition in hippocampus remain uncertain. We used a mouse model of severe TBI [controlled cortical impact (CCI)] to investigate GABAergic signaling in dentate gyrus granule cells (DGGCs). Basal tonic GABA currents were not affected by CCI. However, tonic currents induced by the delta subunit-selective GABA(A) receptor agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP; 10 mu M) were reduced by 44% in DGGCs ipsilateral to CCI (CCI-ipsi), but not in contralateral DGGCs. Reduced THIP currents were apparent one week after injury and persisted up to 15 weeks. The frequency of spontaneous IPSCs (sIPSCs) was reduced in CCI-ipsi cells, but the amplitude and kinetics of sIPSCs were unaffected. Immunohistochemical analysis showed reduced expression of GABA(A) receptor delta subunits and GABA(B) receptor B2 subunits after CCI, by 43% and 40%, respectively. Activation of postsynaptic GABA(B) receptors caused a twofold increase in tonic currents, and this effect was markedly attenuated in CCI-ipsi cells (92% reduction). GABA(B) receptor-activated K+ currents in DGGCs were also significantly reduced in CCI-ipsi cells, confirming a functional deficit of GABA(B) receptors after CCI. Results indicate broad disruption of GABAergic signaling in DGGCs after CCI, with deficits in both phasic and tonic inhibition and GABA(B) receptor function. These changes are predicted to disrupt operation of hippocampal networks and contribute to sequelae of severe TBI, including epilepsy.