Mild Traumatic Brain Injury Induces Structural and Functional Disconnection of Local Neocortical Inhibitory Networks via Parvalbumin Interneuron Diffuse Axonal Injury.
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) interneurons. 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 interneuron 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 ~9% of total tdTomato+ interneurons, representing ~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.
Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Center, PO Box 980709, Richmond, VA 23298-0709, USA.
Michal
M
Vascak
Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Center, PO Box 980709, Richmond, VA 23298-0709, USA.
Xiaotao
X
Jin
Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Center, PO Box 980709, Richmond, VA 23298-0709, USA.
Kimberle M
KM
Jacobs
Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Center, PO Box 980709, Richmond, VA 23298-0709, USA.
John T
JT
Povlishock
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000150:complications* / Q000473:pathology; D020833:Diffuse Axonal Injury / Q000209:etiology* / Q000473:pathology; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005968:Glutamate Decarboxylase / Q000378:metabolism; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019579:Neocortex / Q000473:pathology* / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009433:Neural Inhibition / Q000235:genetics / Q000502:physiology*; D009434:Neural Pathways / Q000473:pathology* / Q000648:ultrastructure; D010320:Parvalbumins / Q000235:genetics / Q000378:metabolism*; D011810:Quinoxalines / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; D010320:Parvalbumins; D011810:Quinoxalines; C118623:Slc32a1 protein, rat; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C056723:FG 9041; C056639:2-amino-5-phosphopentanoic acid; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D014633:Valine