The Journal of neuroscience : the official journal of the Society for Neuroscience
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alpha-Conotoxins Vc1.1 and Rg1A are peptides from the venom of marine Conus snails that are currently in development as a treatment for neuropathic pain. Here we report that the alpha9alpha10 nicotinic acetylcholine receptor-selective conotoxins Vc1.1 and Rg1A potently and selectively inhibit high-voltage-activated (HVA) calcium channel currents in dissociated DRG neurons in a concentration-dependent manner. The post-translationally modified peptides vc1a and [P6O]Vc1.1 were inactive, as were all other alpha-conotoxins tested. ⋯ Preincubation with a variety of selective receptor antagonists demonstrated that only the GABA(B) receptor antagonists, [S-(R*,R*)][-3-[[1-(3,4-dichlorophenyl)ethyl]amino]-2-hydroxy propyl]([3,4]-cyclohexylmethyl) phosphinic acid hydrochloride (2S)-3[[(1S)-1-(3,4-dichlorophenyl)-ethyl]amino-2-hydroxypropyl](phenylmethyl) phosphinic acid and phaclofen, blocked the effect of Vc1.1 and Rg1A on Ca2+ channel currents. Together, the results identify Ca(V)2.2 as a target of Vc1.1 and Rg1A, potentially mediating their analgesic actions. We propose a novel mechanism by which alpha-conotoxins Vc1.1 and Rg1A modulate native N-type (Ca(V)2.2) Ca2+ channel currents, namely acting as agonists via G-protein-coupled GABA(B) receptors.
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Comparative Study
Striate cortical lesions affect deliberate decision and control of saccade: implication for blindsight.
Monkeys with unilateral lesions of the primary visual cortex (V1) can make saccades to visual stimuli in their contralateral ("affected") hemifield, but their sensitivity to luminance contrast is reduced. We examined whether the effects of V1 lesions were restricted to vision or included later stages of visual-oculomotor processing. Monkeys with unilateral V1 lesions were tested with a visually guided saccade task with stimuli in various spatial positions and of various luminance contrasts. ⋯ We modeled the distribution of saccadic reaction times by a modified diffusion model and obtained evidence that the decision threshold for initiation of saccades to the affected hemifield was lower than that for saccades to the normal hemifield. These results suggest that the geniculostriate pathway is crucial for on-line compensatory mechanisms of saccadic control and for decision processes. We propose that these results reflect deficits in deliberate control of visual-oculomotor processing after V1 lesions, which may parallel loss of visual awareness in human blindsight patients.
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Comparative Study
Epigenetic regulation of BDNF gene transcription in the consolidation of fear memory.
Long-term memory formation requires selective changes in gene expression. Here, we determined the contribution of chromatin remodeling to learning-induced changes in brain-derived neurotrophic factor (bdnf) gene expression in the adult hippocampus. ⋯ In addition, NMDA receptor blockade prevented memory-associated alterations in bdnf DNA methylation, resulting in a block of altered bdnf gene expression in hippocampus and a deficit in memory formation. These results suggest epigenetic modification of the bdnf gene as a mechanism for isoform-specific gene readout during memory consolidation.
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Comparative Study
Supraspinal glial-neuronal interactions contribute to descending pain facilitation.
Spinal glial reaction and proinflammatory cytokine induction play an important role in the development of chronic pain states after tissue and nerve injury. The present study investigated the cellular and molecular mechanisms underlying descending facilitation of neuropathic pain with an emphasis on supraspinal glial-neuronal relationships. An early and transient reaction of microglia and prolonged reaction of astrocytes were found after chronic constriction injury (CCI) of the rat infraorbital nerve in the rostral ventromedial medulla (RVM), a major component of brainstem descending pain modulatory circuitry. ⋯ Neutralization of endogenous TNF-alpha and IL-1beta in the RVM significantly reduced CCI-induced behavioral hypersensitivity and attenuated NR1 phosphorylation. Finally, intra-RVM administration of recombinant TNF-alpha or IL-1beta upregulated NR1 phosphorylation and caused a reversible and NMDAR-dependent allodynia in normal rats, further suggesting that TNF-alpha and IL-1beta couple glial hyperactivation with NMDAR function. These studies have addressed a novel contribution of supraspinal astrocytes and associated cytokines as well as central glial-neuronal interactions to the enhancement of descending facilitation of neuropathic pain.
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The initial synapse in the olfactory system is from olfactory nerve (ON) terminals to postsynaptic targets in olfactory bulb glomeruli. Recent studies have disclosed multiple presynaptic factors that regulate this important linkage, but less is known about the contribution of postsynaptic intrinsic conductances to integration at these synapses. The present study demonstrates voltage-dependent amplification of EPSPs in external tufted (ET) cells in response to monosynaptic (ON) inputs. ⋯ However, near resting membrane potentials where I(h) is engaged, IPSPs produce rebound bursts of action potentials. ET cells excite GABAergic PG cells. Thus, the transformation of inhibitory inputs to postsynaptic excitation in ET cells may enhance intraglomerular inhibition of mitral/tufted cells, the main output neurons in the olfactory bulb, and hence shape signaling to olfactory cortex.