The Journal of neuroscience : the official journal of the Society for Neuroscience
-
In visual cortex, NMDA receptor (NMDAR) properties depend primarily on NR2A and NR2B subunits, and NR2 subunit composition changes with age and visual experience. We examined the roles of these NR2 subunits in activity-dependent long-term modification of synaptic responses, which were evoked in layer 2/3 cells by stimulation of layer 4 in rat visual cortical slices. We used theta-burst stimulation (TBS) of presynaptic fibers or low-frequency stimulation paired with postsynaptic depolarization, which has been commonly used to induce NMDAR-dependent long-term potentiation (LTP) in visual cortex. ⋯ Experiments using NR2B selective and NR2 subunit nonselective NMDAR antagonists demonstrated that NR2A- and NR2B-containing NMDARs contribute selectively to inhibitory LTD-field-LTP and excitatory LTP, respectively. In addition, we found that the developmental decline in the NR2B component was paralleled by a decline in the incidence of excitatory LTP, and these declines were both prevented by dark rearing. These results implicate NR2 subunit composition in the regulation of neocortical plasticity and demonstrate differential subunit regulation at inhibitory and excitatory connections.
-
Orexin (ORX)-A is a 33-amino acid peptide with demonstrated roles in the regulation of energy metabolism, autonomic control, and sleep. Orexin receptors (OXRs), OX1R and OX2R, and immunoreactive axons are present in the nucleus tractus solitarius (NTS). We demonstrated previously that bath application of ORX-A depolarizes NTS neurons through activation of a nonselective cationic conductance (NSCC) and inhibition of a sustained potassium current (IK). ⋯ In contrast, 12-O-tetradecanoylphorbol-13-acetate (a PKC agonist) depolarized NTS neurons, and bisindolylmaleimide (BIS), a PKC inhibitor, abolished the depolarizing effects of ORX-A. Finally, voltage-clamp experiments demonstrated that BIS also blocked the activation of NSCC and inhibition of IK by ORX-A in NTS neurons. These results therefore show that the excitatory effects of ORX-A on NTS neurons are mediated through activation of the PLC-PKC-NSCC and -IK signaling pathways, which probably result from OXR-coupled activation of Gq.
-
Critical role for microglial NADPH oxidase in rotenone-induced degeneration of dopaminergic neurons.
Increasing evidence has suggested an important role for environmental toxins such as pesticides in the pathogenesis of Parkinson's disease (PD). Chronic exposure to rotenone, a common herbicide, reproduces features of Parkinsonism in rats. Mechanistically, rotenone-induced dopaminergic neurodegeneration has been associated with both its inhibition of neuronal mitochondrial complex I and the enhancement of activated microglia. ⋯ Furthermore, apocynin attenuated rotenone neurotoxicity only in the presence of microglia from gp91phox+/+ mice. These results indicated that the greatly enhanced neurotoxicity of rotenone was attributed to the release of NADPH oxidase-derived superoxide from activated microglia. This study also suggested that microglial NADPH oxidase may be a promising target for PD treatment.
-
The human immunodeficiency virus type 1 (HIV-1) envelope protein gp120 has been implicated in the pathogenesis of HIV-1 dementia. Thus, inhibition of gp120 activity could reduce HIV toxicity in the brain. We have used primary cultures of rat cerebellar granule cells to examine mechanisms whereby gp120 causes cell death and to characterize neuroprotective agents. gp120 induced a time- and concentration-dependent apoptotic cell death, which was caspase-3-mediated but caspase-1 independent, and was totally blocked by the irreversible caspase-3-like protease inhibitor N-acetyl-Asp-Glu-Val-Asp-chloromethylketone. ⋯ This effect correlated with the ability of BDNF to reduce gp120 internalization and apoptosis. Moreover, BDNF blocked the neurotoxic effect of stromal-derived factor-1alpha, a natural ligand for CXCR4, further establishing a correlation between neuroprotection and downregulation of CXCR4. We propose that BDNF may be a valid therapy to slow down the progression of HIV/gp120-mediated neurotoxicity.
-
Thrombin-induced microglial activation produces degeneration of nigral dopaminergic neurons in vivo.
The present study examined whether thrombin-induced microglial activation could contribute to death of dopaminergic neurons in the rat substantia nigra (SN) in vivo. Seven days after thrombin injection into the SN, tyrosine hydroxylase immunohistochemistry showed a significant loss of nigral dopaminergic neurons. In parallel, thrombin-activated microglia, visualized by immunohistochemical staining using antibodies against the complement receptor type 3 (OX-42) and the major histocompatibility complex class II antigens were also observed in the SN, where degeneration of nigral neurons was found. ⋯ Additional studies demonstrated that extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) were activated in the SN as early as 30 min after thrombin injection, and that these kinases were localized within microglia. Inhibition of ERK1/2 and p38 MAPK reduced iNOS and COX-2 mRNA expression and rescued dopaminergic neurons in the SN. The present results strongly suggest that microglial activation triggered by endogenous compound(s) such as thrombin may be involved in the neuropathological processes of dopaminergic neuronal cell death that occur in Parkinson's disease.