Neuroscience
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Mitogen-activated protein kinases (MAPKs) are important signaling factors in many cellular processes including cell proliferation and survival during development and synaptic plasticity induced by acute nociception in the adult. There is extensive evidence for the involvement of members of the MAPK family, the extracellular signal-regulated kinases 1 and 2 (ERKs 1/2), in the development of acute inflammatory somatic and visceral pain, but their role in the maintenance of chronic pain states is unknown. We have previously shown that ovariectomy of adult mice (OVX) generates a persistent and estrogen-dependent abdominal hyperalgesic state that lasts for several months and is not related to a persistent nociceptive afferent input. ⋯ Administration of slow-release pellets containing 17β-estradiol at week 5 post OVX reversed both the development of the hyperalgesia and the enhanced activation of ERK 1/2, suggesting that this activation, like the hyperalgesic state, was estrogen-dependent. Intrathecal injections of the ERK 1/2 inhibitor U0126 successfully rescued the mice from the abdominal hyperalgesia for up to 24 h after the injection and also reversed the enhanced expression of ERK 1/2. Our study shows, for the first time, activation of ERK 1/2 in the spinal cord matching the time course of an estrogen-dependent chronic hyperalgesic state.
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Developmental dyslexia is a language-based learning disability, and a number of candidate dyslexia susceptibility genes have been identified, including DYX1C1, KIAA0319, and DCDC2. Knockdown of function by embryonic transfection of small hairpin RNA (shRNA) of rat homologues of these genes dramatically disrupts neuronal migration to the cerebral cortex by both cell autonomous and non-cell autonomous effects. Here we sought to investigate the extent of non-cell autonomous effects following in utero disruption of the candidate dyslexia susceptibility gene homolog Dyx1c1 by assessing the effects of this disruption on GABAergic neurons. ⋯ We found untransfected GABAergic neurons (parvalbumin, calretinin, and neuropeptide Y) in the heterotopic collections of neurons in Dyx1c1 shRNA treated animals, supporting the hypothesis of non-cell autonomous effects. In contrast, we found no evidence that the position of the GABAergic neurons that made it to the cerebral cortex was disrupted by the embryonic transfection with any of the constructs. Taken together, these results support the notion that neurons within heterotopias caused by transfection with Dyx1c1 shRNA result from both cell autonomous and non-cell autonomous effects, but there is no evidence to support non-cell autonomous disruption of neuronal position in the cerebral cortex itself.
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Recent studies suggested that acute sound exposure resulting in a temporary threshold shift in young adult animals within a series of maladaptive plasticity changes in central auditory structures. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is involved in post-trauma peripheral hair cell and spiral ganglion cell survival and has been shown to modulate synaptic strength in cochlear nucleus following sound exposure. The present study evaluated levels of BDNF and its receptor (tyrosine kinase B, [TrkB]) in the dorsal cochlear nucleus (DCN) following a unilateral moderate sound exposure in young (7-8 months) and aged (28-29 months) Fischer Brown Norway (FBN) rats. ⋯ Protein levels of the BDNF receptor, TrkB, were also significantly increased in aged but not in young sound-exposed DCN fusiform cells. The present findings suggest a relationship between the up-regulation of BDNF/TrkB and the increase in spontaneous and driven activity previously observed for aged and sound-exposed fusiform cells. This might be due to a selective maladaptive compensatory down-regulation of glycinergic inhibition in DCN fusiform cells.
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Prolactin-releasing peptide (PrRP) is an RF-amide peptide that is believed to be the physiological ligand for the G-protein coupled receptor GPR10. This receptor is highly expressed in the GABAergic principal neurons of the reticular thalamic nucleus (RTN), but the cellular and physiological effects of receptor activation on thalamic function are not yet clear. The present study examined the effects of PrRP on excitatory and inhibitory synaptic transmission in the RTN and the ventrobasal complex (VB) of the thalamus. ⋯ The former represents inhibitory input from RTN neurons to thalamocortical relay cells and the latter a local inhibition produced by RTN axon collaterals. Miniature IPSC analysis revealed that PrRP enhanced release of GABA and thus acted presynaptically. In conclusion, PrRP increases both excitatory and inhibitory synaptic transmission in the thalamus via distinct mechanisms, and the receptors responsible for these actions are in all cases present in the principal neuron of the RTN.
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The mechanism of action of the A2A adenosine receptor agonist 2-p-(2-carboxyethyl) phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS-21680) in the facilitation of spontaneous (isotonic and hypertonic condition) and K+-evoked acetylcholine (ACh) release was investigated in the mouse diaphragm muscles. At isotonic condition, the CGS-21680-induced excitatory effect on miniature end-plate potential (MEPP) frequency was not modified in the presence of CdCl2 and in a medium free of Ca2+ (0Ca2+-EGTA), but it was abolished after buffering the rise of intracellular Ca2+ with 1,2-bis-(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid tetra(acetoxy-methyl) (BAPTA-AM) and when the Ca2+-ATPase inhibitor thapsigargin was used to deplete intracellular Ca2+ stores. CGS-21680 did not have a direct effect on the Ca2+-independent neurotransmitter-releasing machinery, since the modulatory effect on the hypertonic response was also occluded by BAPTA-AM and thapsigargin. ⋯ The blockade of Ca2+ release from endoplasmic reticulum with ryanodine antagonized the facilitating effect of CGS-21680 in control and high K+ concentration. It is concluded that, at the mouse neuromuscular junction, activation of A2A receptors facilitates spontaneous and K+-evoked ACh release by an external Ca2+-independent mechanism but that involves mobilization of Ca2+ from internal stores: during spontaneous ACh release stimulating directly the ryanodine-sensitive stores and, at high K+, probably modulating the L-type VDCCs which may cause the opening of the ryanodine receptors that would be directly coupled to the channels. In both cases, Ca2+ released from the endoplasmic reticulum would be capable of activating the exocytotic machinery, thus producing facilitation of ACh release.