The ependyma of the adult spinal cord is a latent stem cell niche that is reactivated by spinal cord injury contributing new cells to the glial scar. The cellular events taking place in the early stages of the reaction of the ependyma to injury remain little understood. Ependymal cells are functionally heterogeneous with a mitotically active subpopulation lining the lateral domains of the central canal (CC) that are coupled via gap junctions. Gap junctions and connexin hemichannels are key regulators of the biology of neural progenitors during development and in adult neurogenic niches. Thus, we hypothesized that communication via connexins in the CC is developmentally regulated and may play a part in the reactivation of this latent stem cell niche after injury. To test these possibilities, we combined patch-clamp recordings of ependymal cells with immunohistochemistry for various connexins in the neonatal and the adult (P Ͼ 90) normal and injured spinal cord of male and female mice. We find that coupling among ependymal cells is downregulated as postnatal development proceeds but increases after injury, resembling the immature CC. The increase in gap junction coupling in the adult CC was paralleled by upregulation of connexin 26, which correlated with the resumption of proliferation and a reduction of connexin hemichannel activity. Connexin blockade reduced the injury-induced proliferation of ependymal cells. Our findings suggest that connexins are involved in the early reaction of ependymal cells to injury, representing a potential target to improve the contribution of the CC stem cell niche to repair.
The ependyma of the spinal cord is currently proposed as a latent neural stem cell niche. This chapter discusses recent knowledge on the developmental origin and nature of the heterogeneous population of cells that compose this stem cell microenviroment, their diverse physiological properties and regulation. The chapter also reviews relevant data on the ependymal cells as a source of plasticity for spinal cord repair.
Non-technical summary Neurogenesis is tightly regulated by epigenetic factors that assure the correct assembly of neural circuits. Neurotransmitters play a fundamental role in this type of control. We show that GABA signals on progenitors and immature neurones within a neurogenic niche around the central canal (CC) of the turtle spinal cord. GABA depolarized progenitors whereas the effect on immature neurones varied from excitation to inhibition. In both cell types GABA A receptor activation induced an increase in intracellular calcium. Our findings imply that GABAergic signalling around the CC shares fundamental properties with those in the embryo and adult neurogenic niches in the brain, suggesting that GABA is part of the mechanisms regulating the production and integration of neurones to already operational spinal circuits. Understanding the GABAergic modulation of progenitors and neuroblasts may provide useful clues about key mechanisms needed for functional neurogenesis in the spinal cord.Abstract The region that surrounds the central canal (CC) in the turtle spinal cord is a neurogenic niche immersed within already functional circuits, where radial glia expressing brain lipid binding protein (BLBP) behave as progenitors. The behaviour of both progenitors and neuroblasts within adult neurogenic niches must be regulated to maintain the functional stability of the host circuit. In the brain, GABA plays a major role in this kind of regulation but little is known about GABAergic signalling in neurogenic niches of the postnatal spinal cord. Here we explored the action of GABA around the CC of the turtle spinal cord by combining patch-clamp recordings of CC-contacting cells, immunohistochemistry for key components of GABAergic signalling and Ca 2+ imaging. Two potential sources of GABA appeared around the CC: GABAergic terminals and CC-contacting neurones. GABA depolarized BLBP + progenitors via GABA transporter-3 (GAT3) and/or GABA A receptors. In CC-contacting neurones, GABA A receptor activation generated responses ranging from excitation to inhibition. This functional heterogeneity appeared to originate from different ratios of activity of the Na + -K + -2Cl − co-transporter (NKCC1) and the K + -Cl − co-transporter (KCC2). In both progenitors and immature neurones, GABA induced an increase in intracellular Ca 2+ that required extracellular Ca 2+ and was blocked by the selective GABA A receptor antagonist gabazine. Our study shows that GABAergic signalling around the CC shares fundamental properties with those in the embryo and adult neurogenic niches, suggesting that GABA may be part of the mechanisms regulating the production and integration of neurones within operational spinal circuits in the turtle.
Non-technical summary The dorsal horn of the spinal cord is the first site in the central nervous system where painful sensory information is processed before transmission to the brain. In vitro recordings in spinal slices established that this processing relies on both plasticity of synaptic connections and intrinsic electrical properties of dorsal horn neurones (DHNs). DHNs may generate plateau potentials, which underlie intense discharges and long-lasting after-discharges in response to a brief stimulation, and represent a putative endogenous mechanism for amplification of painful sensory inputs. Using patch-clamp recordings in the anaesthetized adult rat, we show that DHNs do generate plateau potentials in vivo, which shape their responses to natural sensory stimulation. Moreover, we give direct evidence for the involvement of these amplification properties in both short-term (windup) and long-term sensitisation associated with neuropathic pain, raising the possibility that plateau potentials could be putative therapeutic targets to control spinal component of neuropathic pain.Abstract The dorsal horn of the spinal cord is the first central relay where nociceptive inputs are processed. Based on the expression and modulation of intrinsic electrophysiological properties in in vitro slice preparations, dorsal horn neurones (DHNs) display different discharge patterns (tonic, plateau or rhythmic), which shape the neurone's response to sensory inputs. However, it is unclear whether intrinsic properties play any role in sensory processing in vivo. Using in vivo patch clamp recordings in the adult rat, we here examine whether these intrinsic properties are present, and to what extent they determine the DHN response to natural stimulation. We focused primarily on wide dynamic range neurones in deep laminae. These cells displayed a multicomponent peripheral receptive field, comprising an excitatory firing zone, a low-probability firing fringe, and adjacent inhibitory zones. Deep DHNs presented similar intrinsic properties to those observed in vitro, including plateau potentials. These plateaus, underlying high frequency accelerating discharges and after-discharges, were triggered by mechanical stimulation of the excitatory receptive field. Persistent activities induced by activation of plateau potentials were interrupted by stimulation of peripheral inhibitory zones. Moreover, we show that plateau activation is necessary for the expression of windup in response to repetitive, nociceptive stimulation. Finally, using the spinal nerve ligation model of neuropathy, we demonstrate a significant increase in the proportion of plateau neurones in deep dorsal laminae. Our data, therefore, establish that C. Reali and P. Fossat contributed equally to this work; R. E. Russo and F. Nagy made the same intellectual contribution. intrinsic amplification properties are expressed within intact spinal circuits and suggest their involvement in neuropathy-induced hyperexcitability of deep DHNs.
This paper deals with the cytological organization of the central gelatinosa (CG) in the spinal cord of juvenile (2-12 months) turtles. We found two main cell classes in the CG: one with characteristics of immature neurons, the other identified as radial glia (RG). The cells surrounding the central canal formed radial conglomerates in such a way that the RG lamellae covered the immature neurons. We found three major subpopulations of RG that expressed S-100, glial fibrillary acidic protein, or both proteins. Electron microscopic images showed gap junctions interconnecting RG. As with the mammalian neuroepithelial cells, most CG cells displayed intrinsic polarity expressed by structural and molecular differences between the most apical and basal cell compartments. The apical zone was characterized by the occurrence of a single cilium associated with a conspicuous centrosomal complex. We found a prominent expression of the PCM-1 centrosomal protein concentrated close to the central canal lumen. In the particular case of RG, the peripheral end feet contacted the subpial basement membrane. We also found "transitional cell forms" difficult to classify by the usual imaging approaches. Functional clues obtained by patch-clamp recordings of CG cells defined some of them as already committed to follow the neuronal lineage, whereas others had properties of less mature or migrating cells. The CG appeared as a richly innervated region receiving terminal branches from nerve plexuses expressing gamma-aminobutyric acid, serotonin, and glutamate. The results presented here support our previous studies indicating that the CG is an extended neurogenic niche along the spinal cord of turtles.
Traumatic injury of the spinal cord leads to devastating conditions that affect ~2.5 million people worldwide. This is because the mammalian spinal cord reacts to injury with only limited endogenous repair. Functional restoration requires the replacement of lost cells, the growth and navigation of regenerating axons on a permissive scaffold and axon re-myelination. The manipulation of endogenous spinal stem cells is regarded as a potential strategy to restore function. For this type of therapy it is necessary to determine the molecular and functional mechanisms regulating the proliferation, migration and differentiation of adult spinal progenitors. The spinal cord of animal models in which self-repair normally occurs may provide some clues. Salamanders, some fish and turtles regenerate their spinal cord after massive injury, achieving substantial functional recovery. This regeneration is orchestrated by progenitors that line the central canal (CC). Although mammals have lost the ability for self-repair, some cells in the CC react to injury by proliferating and migrating toward the lesion, where most become astrocytes in the core of the scar. Thus, CC-contacting progenitors in mammals have "latent" programs for endogenous repair of the spinal cord. Progenitor-like cells in the CC are functionally organized in lateral and midline domains, with heterogeneous molecular and membrane properties that represent targets for modulation. Understanding the mechanisms by which CC-can be manipulated will give valuable clues for endogenous spinal cord repair leading to successful functional recovery.
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