Mild Traumatic Brain Injury Induces Structural and Functional Disconnection of Local Neocortical Inhibitory Networks via Parvalbumin Interneuron Diffuse Axonal Injury

被引:35
作者
Vascak, Michal [1 ]
Jin, Xiaotao [1 ]
Jacobs, Kimberle M. [1 ]
Povlishock, John T. [1 ]
机构
[1] Virginia Commonwealth Univ, Med Ctr, Dept Anat & Neurobiol, POB 980709, Richmond, VA 23298 USA
基金
美国国家卫生研究院;
关键词
concussion; diffuse axonal injury; excitation/inhibition; fast-spiking; gray matter; AMYLOID PRECURSOR PROTEIN; NONMISSILE HEAD-INJURY; WHITE-MATTER; CEREBRAL-CORTEX; CORTICAL INTERNEURONS; GAMMA-OSCILLATIONS; POSTTRAUMATIC EPILEPSY; COGNITIVE IMPAIRMENT; ANTIGEN RETRIEVAL; NEURONAL CIRCUITS;
D O I
10.1093/cercor/bhx058
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Diffuse axonal injury (DAI) plays a major role in cortical network dysfunction posited to cause excitatory/inhibitory imbalance after mild traumatic brain injury (mTBI). Current thought holds that white matter (WM) is uniquely vulnerable to DAI. However, clinically diagnosed mTBI is not always associated with WM DAI. This suggests an undetected neocortical pathophysiology, implicating GABAergic interneurons. To evaluate this possibility, we used mild central fluid percussion injury to generate DAI in mice with Cre-driven tdTomato labeling of parvalbumin (PV) intemeurons. We followed tdTomato+ profiles using confocal and electron microscopy, together with patch-clamp analysis to probe for DAI-mediated neocortical GABAergic interneuron disruption. Within 3 h post-mTBI tdTomato+ perisomatic axonal injury (PSAI) was found across somatosensory layers 2-6. The DAI marker amyloid precursor protein colocalized with GAD67 immunoreactivity within tdTomato+ PSAI, representing the majority of GABAergic intemeuron DAI. At 24 h post-mTBI, we used phospho-c-Jun, a surrogate DAI marker, for retrograde assessments of sustaining somas. Via this approach, we estimated DAI occurs in similar to 9% of total tdTomato+ interneurons, representing similar to 14% of pan-neuronal DAI. Patch-clamp recordings of tdTomato+ interneurons revealed decreased inhibitory transmission. Overall, these data show that PV interneuron DAI is a consistent and significant feature of experimental mTBI with important implications for cortical network dysfunction.
引用
收藏
页码:1625 / 1644
页数:20
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