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Axonal remodeling for motor recovery after traumatic brain injury requires downregulation of γ-aminobutyric acid signaling.

Lee S, Ueno M, Yamashita T - Cell Death Dis (2011)

Bottom Line: Here, we show that altered γ-aminobutyric acid (GABA) signaling is crucial for axonal remodeling of the contralesional cortex after traumatic brain injury.Further, muscimol infusion greatly suppressed the axonal sprouting into the denervated side of the cervical spinal cord.In conclusion, recovery of motor function and axonal remodeling of the CST following cortical injury requires suppressed GABA(A)R subunit expression and decreased GABAergic signaling.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.

ABSTRACT
Remodeling of the remnant neuronal network after brain injury possibly mediates spontaneous functional recovery; however, the mechanisms inducing axonal remodeling during spontaneous recovery remain unclear. Here, we show that altered γ-aminobutyric acid (GABA) signaling is crucial for axonal remodeling of the contralesional cortex after traumatic brain injury. After injury to the sensorimotor cortex in mice, we found a significant decrease in the expression of GABA(A)R-α1 subunits in the intact sensorimotor cortex for 2 weeks. Motor functions, assessed by grid walk and cylinder tests, spontaneously improved in 4 weeks after the injury to the sensorimotor cortex. With motor recovery, corticospinal tract (CST) axons from the contralesional cortex sprouted into the denervated side of the cervical spinal cord at 2 and 4 weeks after the injury. To determine the functional implications of the changes in the expression of GABA(A)R-α1 subunits, we infused muscimol, a GABA R agonist, into the contralesional cortex for a week after the injury. Compared with the vehicle-treated mice, we noted significantly inhibited recovery in the muscimol-treated mice. Further, muscimol infusion greatly suppressed the axonal sprouting into the denervated side of the cervical spinal cord. In conclusion, recovery of motor function and axonal remodeling of the CST following cortical injury requires suppressed GABA(A)R subunit expression and decreased GABAergic signaling.

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Spontaneous recovery of motor function after brain injury is suppressed by muscimol infusion into the contralesional cortex. (a and b) Spontaneous recovery of forelimb motor function in the grid walk (a) and cylinder (b) tests (sham group, dotted line; injured group, solid line; n=7, each group). (c and d) Inhibition of spontaneous recovery of forelimb motor function by muscimol infusion in the grid walk (c) and cylinder (d) tests (saline-treated group, dotted line; muscimol-treated group, solid line). The data represent the mean±S.D. (vehicle n=7, muscimol n=12); *P<0.05, **P<0.01 versus the controls (two-way repeated measure ANOVA followed by Tukey–Kramer test)
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fig3: Spontaneous recovery of motor function after brain injury is suppressed by muscimol infusion into the contralesional cortex. (a and b) Spontaneous recovery of forelimb motor function in the grid walk (a) and cylinder (b) tests (sham group, dotted line; injured group, solid line; n=7, each group). (c and d) Inhibition of spontaneous recovery of forelimb motor function by muscimol infusion in the grid walk (c) and cylinder (d) tests (saline-treated group, dotted line; muscimol-treated group, solid line). The data represent the mean±S.D. (vehicle n=7, muscimol n=12); *P<0.05, **P<0.01 versus the controls (two-way repeated measure ANOVA followed by Tukey–Kramer test)

Mentions: The temporal downregulation of GABAAR-α1 subunit expression in the contralesional cortex suggests that the activity of these neurons was upregulated. Actually, we found elevated expression of one neuronal activity-dependent gene, alivin-1,12 in the contralesional cortex (Supplementary Figure 1E). Thus, we next tried to explore the functional implications of this phenomenon. In accordance with previous reports,3 the injured mice showed spontaneous functional recovery after the initial motor deficits. We assessed the functional recovery with two motor tests. Although the ability to walk on a grid was severely impaired at one day after the injury, it gradually improved until 4 weeks after the injury (Figure 3a). In the cylinder test, the injured mice showed significant forelimb-use asymmetries for vertical exploration during the first week after the injury, especially reduced use of the impaired left forelimb (Figure 3b, P<0.01). The independent or simultaneous use of the impaired forelimb gradually increased until 4 weeks after the injury, indicating that the function of this forelimb spontaneously recovered (Figure 3b).


Axonal remodeling for motor recovery after traumatic brain injury requires downregulation of γ-aminobutyric acid signaling.

Lee S, Ueno M, Yamashita T - Cell Death Dis (2011)

Spontaneous recovery of motor function after brain injury is suppressed by muscimol infusion into the contralesional cortex. (a and b) Spontaneous recovery of forelimb motor function in the grid walk (a) and cylinder (b) tests (sham group, dotted line; injured group, solid line; n=7, each group). (c and d) Inhibition of spontaneous recovery of forelimb motor function by muscimol infusion in the grid walk (c) and cylinder (d) tests (saline-treated group, dotted line; muscimol-treated group, solid line). The data represent the mean±S.D. (vehicle n=7, muscimol n=12); *P<0.05, **P<0.01 versus the controls (two-way repeated measure ANOVA followed by Tukey–Kramer test)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3101813&req=5

fig3: Spontaneous recovery of motor function after brain injury is suppressed by muscimol infusion into the contralesional cortex. (a and b) Spontaneous recovery of forelimb motor function in the grid walk (a) and cylinder (b) tests (sham group, dotted line; injured group, solid line; n=7, each group). (c and d) Inhibition of spontaneous recovery of forelimb motor function by muscimol infusion in the grid walk (c) and cylinder (d) tests (saline-treated group, dotted line; muscimol-treated group, solid line). The data represent the mean±S.D. (vehicle n=7, muscimol n=12); *P<0.05, **P<0.01 versus the controls (two-way repeated measure ANOVA followed by Tukey–Kramer test)
Mentions: The temporal downregulation of GABAAR-α1 subunit expression in the contralesional cortex suggests that the activity of these neurons was upregulated. Actually, we found elevated expression of one neuronal activity-dependent gene, alivin-1,12 in the contralesional cortex (Supplementary Figure 1E). Thus, we next tried to explore the functional implications of this phenomenon. In accordance with previous reports,3 the injured mice showed spontaneous functional recovery after the initial motor deficits. We assessed the functional recovery with two motor tests. Although the ability to walk on a grid was severely impaired at one day after the injury, it gradually improved until 4 weeks after the injury (Figure 3a). In the cylinder test, the injured mice showed significant forelimb-use asymmetries for vertical exploration during the first week after the injury, especially reduced use of the impaired left forelimb (Figure 3b, P<0.01). The independent or simultaneous use of the impaired forelimb gradually increased until 4 weeks after the injury, indicating that the function of this forelimb spontaneously recovered (Figure 3b).

Bottom Line: Here, we show that altered γ-aminobutyric acid (GABA) signaling is crucial for axonal remodeling of the contralesional cortex after traumatic brain injury.Further, muscimol infusion greatly suppressed the axonal sprouting into the denervated side of the cervical spinal cord.In conclusion, recovery of motor function and axonal remodeling of the CST following cortical injury requires suppressed GABA(A)R subunit expression and decreased GABAergic signaling.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.

ABSTRACT
Remodeling of the remnant neuronal network after brain injury possibly mediates spontaneous functional recovery; however, the mechanisms inducing axonal remodeling during spontaneous recovery remain unclear. Here, we show that altered γ-aminobutyric acid (GABA) signaling is crucial for axonal remodeling of the contralesional cortex after traumatic brain injury. After injury to the sensorimotor cortex in mice, we found a significant decrease in the expression of GABA(A)R-α1 subunits in the intact sensorimotor cortex for 2 weeks. Motor functions, assessed by grid walk and cylinder tests, spontaneously improved in 4 weeks after the injury to the sensorimotor cortex. With motor recovery, corticospinal tract (CST) axons from the contralesional cortex sprouted into the denervated side of the cervical spinal cord at 2 and 4 weeks after the injury. To determine the functional implications of the changes in the expression of GABA(A)R-α1 subunits, we infused muscimol, a GABA R agonist, into the contralesional cortex for a week after the injury. Compared with the vehicle-treated mice, we noted significantly inhibited recovery in the muscimol-treated mice. Further, muscimol infusion greatly suppressed the axonal sprouting into the denervated side of the cervical spinal cord. In conclusion, recovery of motor function and axonal remodeling of the CST following cortical injury requires suppressed GABA(A)R subunit expression and decreased GABAergic signaling.

Show MeSH
Related in: MedlinePlus