Experimental neurology
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Experimental neurology · May 2015
NMDA receptor blockade in the developing cortex induces autophagy-mediated death of immature cortical GABAergic interneurons: An ex vivo and in vivo study in Gad67-GFP mice.
In neonates, excitotoxicity is a major process involved in hypoxic-ischemic brain lesions, and several research groups have suggested the use of NMDA antagonists for neuroprotection. However, despite their clinical interest, there is more and more evidence suggesting that, in the immature brain, these molecules exert deleterious actions on migrating GABAergic interneurons by suppressing glutamatergic trophic inputs. Consequently, preventing the side effects of NMDA antagonists would be therapeutically useful. ⋯ Together, these data suggest that, in the developing cortex, the suppression of glutamatergic inputs through NMDA receptor inhibition results in the impairment of the autophagic flux and the subsequent switch to apoptotic death of immature GABAergic interneurons. The concomitant inhibition of autophagy prevents this pro-apoptotic action of the NMDA blocker and favors the long-term rescue of GABAergic interneurons without interfering with its neuroprotective actions. The use of autophagy modulators in the developing brain would create new opportunities to prevent the side effects of NMDA antagonists used for neuroprotection or anesthesia.
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Experimental neurology · May 2015
Involvement of medullary GABAergic system in extraterritorial neuropathic pain mechanisms associated with inferior alveolar nerve transection.
In order to determine if the functional changes in the GABAergic system in the trigeminal spinal subnucleus caudalis (Vc) are involved in the mechanisms underlying extraterritorial neuropathic pain in the orofacial region following inferior alveolar nerve transection (IANX), mechanical noxious behavior, phosphorylated extracellular signal-regulated kinase (pERK) immunohistochemistry and single neuronal activity were analyzed in vesicular GABA transporter (VGAT)-VenusA rats expressing fluorescent protein and the VGAT in Vc neurons. The number of VGAT-VenusA positive neurons was significantly reduced in IANX rats than naive and sham rats at 7days after nerve transection. The number of VGAT-VenusA positive pERK-immunoreactive (IR) cells was significantly increased in IANX rats at 21days after IAN transection compared with naive and sham rats. ⋯ The head-withdrawal threshold (HWT) to mechanical stimulation of the whisker pad skin was significantly decreased in IANX rats compared with sham rats on days 7 and 21 after IANX. The significant reduction of the HWT and significant increase in the number of VGAT-VenusA negative pERK-IR cells were observed in KCC2 blocker R-DIOA-injected rats compared with vehicle-injected rats on day 21 after sham treatment. These findings revealed that GABAergic Vc neurons might be reduced in their number at the early period after IANX and the functional changes might occur in GABAergic neurons from inhibitory to excitatory at the late period after IANX, suggesting that the neuroplastic changes occur in the GABAergic neuronal network in the Vc due to morphological and functional changes at different time periods following IANX and resulting in the extraterritorial neuropathic pain in the orofacial region following trigeminal nerve injury.
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Experimental neurology · May 2015
Mirror-image pain after nerve reconstruction in rats is related to enhanced density of epidermal peptidergic nerve fibers.
Mirror-image pain is a phenomenon in which unprovoked pain is detected on the uninjured contralateral side after unilateral nerve injury. Although it has been implicated that enhanced production of nerve growth factor (NGF) in the contralateral dorsal root ganglion is important in the development of mirror-image pain, it is not known if this is related to enhanced expression of nociceptive fibers in the contralateral skin. Mechanical and thermal sensitivity in the contralateral hind paw was measured at four different time points (5, 10, 20 and 30weeks) after transection and immediate end-to-end reconstruction of the sciatic nerve in rats. ⋯ We conclude that changes in skin innervation and sensitivity are present on the uninjured corresponding side in a transient pain model. Therefore, the contralateral side cannot serve as control. Moreover, the current study confirms the involvement of the peripheral nervous system in the development of mirror-image pain.
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Experimental neurology · Apr 2015
Daily acute intermittent hypoxia elicits functional recovery of diaphragm and inspiratory intercostal muscle activity after acute cervical spinal injury.
A major cause of mortality after spinal cord injury is respiratory failure. In normal rats, acute intermittent hypoxia (AIH) induces respiratory motor plasticity, expressed as diaphragm (Dia) and second external intercostal (T2 EIC) long-term facilitation (LTF). Dia (not T2 EIC) LTF is enhanced by systemic adenosine 2A (A2A) receptor inhibition in normal rats. We investigated the respective contributions of Dia and T2 EIC to daily AIH-induced functional recovery of breathing capacity with/without A2A receptor antagonist (KW6002, i.p.) following C2 hemisection (C2HS). Rats received daily AIH (dAIH: 10, 5-min episodes, 10.5% O2; 5-min normoxic intervals; 7 successive days beginning 7days post-C2HS) or daily normoxia (dNx) with/without KW6002, followed by weekly (reminder) presentations for 8weeks. Ventilation and EMGs from bilateral diaphragm and T2 EIC muscles were measured with room air breathing (21% O2) and maximum chemoreceptor stimulation ( ⋯ 7% CO2, 10.5% O2). dAIH increased tidal volume (VT) in C2HS rats breathing room air (dAIH+vehicle: 0.47±0.02, dNx+vehicle: 0.40±0.01ml/100g; p<0.05) and MCS (dAIH+vehicle: 0.83±0.01, dNx+vehicle: 0.73±0.01ml/100g; p<0.001); KW6002 had no significant effect. dAIH enhanced contralateral (uninjured) diaphragm EMG activity, an effect attenuated by KW6002, during room air breathing and MCS (p<0.05). Although dAIH enhanced contralateral T2 EIC EMG activity during room air breathing, KW6002 had no effect. dAIH had no statistically significant effects on diaphragm or T2 EIC EMG activity ipsilateral to injury. Thus, two weeks post-C2HS: 1) dAIH enhances breathing capacity by effects on contralateral diaphragm and T2 EIC activity; and 2) dAIH-induced recovery is A2A dependent in diaphragm, but not T2 EIC. Daily AIH may be a useful in promoting functional recovery of breathing capacity after cervical spinal injury, but A2A receptor antagonists (e.g. caffeine) may undermine its effectiveness shortly after injury.
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Experimental neurology · Apr 2015
Overexpression of GRK6 rescues L-DOPA-induced signaling abnormalities in the dopamine-depleted striatum of hemiparkinsonian rats.
l-DOPA therapy in Parkinson's disease often results in side effects such as l-DOPA-induced dyskinesia (LID). Our previous studies demonstrated that defective desensitization of dopamine receptors caused by decreased expression of G protein-coupled receptor kinases (GRKs) plays a role. Overexpression of GRK6, the isoform regulating dopamine receptors, in parkinsonian rats and monkeys alleviated LID and reduced LID-associated changes in gene expression. ⋯ Finally, GRK6 reduced accumulation of ΔFosB in the lesioned striatum, the effect that paralleled a decrease in locomotor sensitization to l-DOPA in GRK6-expressing rats. The results suggest that elevated GRK6 facilitate desensitization of DA receptors, thereby normalizing of the activity of multiple signaling pathways implicated in LID. Thus, improving the regulation of dopamine receptor function via the desensitization mechanism could be an effective way of managing LID.