To study the postnatal development of nociceptive synaptic inputs in the superficial dorsal horn of the neonatal rat spinal
cord, we examined the effect of capsaicin and menthol on glutamatergic ...mEPSCs in postnatal day (P) 0â1, P5â6 and P9â11 slices
of spinal cord. Capsaicin (100 n m to 2 μ m ) increased the mEPSC frequency in a concentration-dependent manner at all ages tested, with a significant enhancement of
the effect between P5 and P10. This effect was sensitive to vanilloid receptor (VR) antagonists. The elevation in mEPSC frequency
occurred at concentrations of capsaicin (100 n m ) that did not alter the distribution of mEPSC amplitudes and was abolished by a dorsal rhizotomy, demonstrating that capsaicin
acts via presynaptic VR1 receptors localized on primary afferents. Menthol significantly increased the mEPSC frequency with
a similar developmental pattern to capsaicin without consistently affecting mEPSC amplitude. The increase in mEPSC frequency
following capsaicin did not depend on transmembrane calcium influx since it persisted in zero Ca 2+ o . The facilitation of spontaneous glutamate release by capsaicin was sufficient to evoke action potentials in neonatal dorsal
horn neurons but was accompanied by a block of EPSCs evoked by electrical stimulation of the dorsal root. These results indicate
that VR1-expressing nociceptive primary afferents form functional synaptic connections in the superficial dorsal horn from
birth and that activation of the VR1 receptor increases spontaneous glutamate release via an undetermined mechanism. In addition,
the data suggest that immature primary afferents express functional menthol receptors that are capable of modulating transmitter
release. These results have important functional implications for infant pain processing.
NMDA receptors have the potential to produce complex activity-dependent regulation of transmitter release when localized presynaptically. In the somatosensory system, NMDA receptors have been ...immunocytochemically detected on presynaptic terminals of primary afferents, and these have been proposed to drive release of substance P from central terminals of a subset of nociceptors in the spinal cord dorsal horn. Here we report that functional NMDA receptors are indeed present at or near the central terminals of primary afferent fibers. Furthermore, we show that activation of these presynaptic receptors results in an inhibition of glutamate release from the terminals. Some of these NMDA receptors may be expressed in the preterminal axon and regulate the extent to which action potentials invade the extensive central arborizations of primary sensory neurons.
Brain organoids are in vitro three-dimensional (3D) self-organized neural structures, which can enable disease modeling and drug screening. However, their use for standardized large-scale drug ...screening studies is limited by their high batch-to-batch variability, long differentiation time (10–20 weeks), and high production costs. This is particularly relevant when brain organoids are obtained from human induced pluripotent stem cells (iPSCs). Here, we developed, for the first time, a highly standardized, reproducible, and fast (5 weeks) murine brain organoid model starting from embryonic neural stem cells. We obtained brain organoids, which progressively differentiated and self-organized into 3D networks of functional neurons with dorsal forebrain phenotype. Furthermore, by adding the morphogen WNT3a, we generated brain organoids with specific hippocampal region identity. Overall, our results showed the establishment of a fast, robust and reproducible murine 3D in vitro brain model that may represent a useful tool for high-throughput drug screening and disease modeling.
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•Murine embryonic NSCs are able to self-organize into brain organoids•Murine brain organoids mature in 32 days, showing dorsal forebrain identity•Brain organoids develop 3D network of functional neurons•WNT3a supplementation induces specific hippocampal brain region identity
Biological sciences; Neuroscience; Cell biology; Developmental biology
No direct evidence has been found for expression of functional AMPA receptors by dorsal root ganglion neurons despite immunocytochemical evidence suggesting they are present. Here we report evidence ...for expression of functional AMPA receptors by a subpopulation of dorsal root ganglion neurons. The AMPA receptors are most prominently located near central terminals of primary afferent fibers. AMPA and kainate receptors were detected by recording receptor-mediated depolarization of the central terminals under selective pharmacological conditions. We demonstrate that activation of presynaptic AMPA receptors by exogenous agonists causes inhibition of glutamate release from the terminals, possibly via primary afferent depolarization (PAD). These results challenge the traditional view that GABA and GABA
A receptors exclusively mediate PAD, and indicate that PAD is also mediated by glutamate acting on presynaptically localized AMPA and kainate receptors.
BDNF as a pain modulator Merighi, Adalberto; Salio, Chiara; Ghirri, Alessia ...
Progress in neurobiology,
07/2008, Letnik:
85, Številka:
3
Journal Article
Recenzirano
Odprti dostop
At least some neurotrophins may be powerful modulators of synapses, thereby influencing short- and long-term synaptic efficiency. BDNF acts at central synapses in pain pathways both at spinal and ...supraspinal levels. Neuronal synthesis, subcellular storage/co-storage and release of BDNF at these synapses have been characterized on anatomical and physiological grounds, in parallel with trkB (the high affinity BDNF receptor) distribution. Histological and functional evidence has been provided, mainly from studies on acute slices and intact animals, that BDNF modulates fast excitatory (glutamatergic) and inhibitory (GABAergic/glycinergic) signals, as well as slow peptidergic neurotrasmission in spinal cord. Recent studies have unraveled some of the neuronal circuitries and mechanisms involved, highlighting the key role of synaptic glomeruli in lamina II as the main sites for such a modulation.
Presynaptic GABA
receptors (GABA
Rs) are highly expressed in dorsal root ganglion neurons and spinal cord dorsal horn. GABA
Rs located in superficial dorsal horn play an important antinociceptive ...role, by acting at both pre- and postsynaptic sites. GABA
Rs expressed in deep dorsal horn could be involved in the processing of touch sensation and possibly in the generation of tactile allodynia in chronic pain. The objective of this study was to characterize the morphological and functional properties of GABA
Rs expressed on Aβ fibers projecting to lamina III/IV and to understand their role in modulating excitatory synaptic transmission. We performed high-resolution electron microscopic analysis, showing that GABA
subunit is expressed on 71.9% of terminals in rat lamina III-IV. These terminals were engaged in axodendritic synapses and, for the 46%, also expressed glutamate immunoreactivity. Monosynaptic excitatory postsynaptic currents, evoked by Aβ fiber stimulation and recorded from lamina III/IV neurons in spinal cord slices, were strongly depressed by application of baclofen (0.1-2.5 µM), acting as a presynaptic modulator. Application of the GABA
R antagonist CGP 55845 caused, in a subpopulation of neurons, the potentiation of the first of two excitatory postsynaptic currents recorded with the paired-pulse protocol, showing that GABA
Rs are endogenously activated. A decrease in the paired-pulse ratio accompanied the effect of CGP 55845, implying the involvement of presynaptic GABA
Rs. CGP 55845 facilitated only the first excitatory postsynaptic current also during a train of four consecutive stimuli applied to Aβ fibers. These results suggest that GABA
Rs tonically inhibit glutamate release from Aβ fibers at a subset of synapses in deep dorsal horn. This modulation specifically affects only the early phase of synaptic excitation in lamina III-IV neurons.
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