Opposite, bidirectional shifts in excitation and inhibition in specific types of dorsal horn interneurons are associated with spasticity and pain post-SCI
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Spasticity, a common complication after spinal cord injury (SCI), is frequently accompanied by chronic pain. The physiological origin of this pain (critical to its treatment) remains unknown, although spastic motor dysfunction has been related to the hyperexcitability of motoneurons and to changes in spinal sensory processing. Here we show that the pain mechanism involves changes in sensory circuits of the dorsal horn (DH) where nociceptive inputs integrate for pain processing. Spasticity is associated with the DH hyperexcitability resulting from an increase in excitation and disinhibition occurring in two respective types of sensory interneurons. In the tonic-firing inhibitory lamina II interneurons, glutamatergic drive was reduced while glycinergic inhibition was potentiated. In contrast, excitatory drive was boosted to the adapting-firing excitatory lamina II interneurons while GABAergic and glycinergic inhibition were reduced. Thus, increased activity of excitatory DH interneurons coupled with the reduced excitability of inhibitory DH interneurons post-SCI could provide a neurophysiological mechanism of central sensitization and chronic pain associated with spasticity.Keywords:
Interneuron
Disinhibition
Gamma-Aminobutyric Acid
Premovement neuronal activity
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Abstract The impact of GABAergic transmission on neuronal excitability depends on the Cl − -gradient across membranes. However, the Cl − -fluxes through GABA A receptors alter the intracellular Cl − concentration ([Cl − ] i ) and in turn attenuate GABAergic responses, a process termed ionic plasticity. Recently it has been shown that coincident glutamatergic inputs significantly affect ionic plasticity. Yet how the [Cl − ] i changes depend on the properties of glutamatergic inputs and their spatiotemporal relation to GABAergic stimuli is unknown. To investigate this issue, we used compartmental biophysical models of Cl − dynamics simulating either a simple ball-and-stick topology or a reconstructed immature CA3 neuron. These computational experiments demonstrated that glutamatergic co-stimulation enhances GABA receptor-mediated Cl − influx at low and attenuates or reverses the Cl − efflux at high initial [Cl − ] i . The size of glutamatergic influence on GABAergic Cl − -fluxes depends on the conductance, decay kinetics, and localization of glutamatergic inputs. Surprisingly, the glutamatergic shift in GABAergic Cl − -fluxes is invariant to latencies between GABAergic and glutamatergic inputs over a substantial interval. In agreement with experimental data, simulations in a reconstructed CA3 pyramidal neuron with physiological patterns of correlated activity revealed that coincident glutamatergic synaptic inputs contribute significantly to the activity-dependent [Cl − ] i changes. Whereas the influence of spatial correlation between distributed glutamatergic and GABAergic inputs was negligible, their temporal correlation played a significant role. In summary, our results demonstrate that glutamatergic co-stimulation had a substantial impact on ionic plasticity of GABAergic responses, enhancing the destabilization of GABAergic inhibition in the mature nervous systems, but suppressing GABAergic [Cl − ] i changes in the immature brain. Therefore, glutamatergic shift in GABAergic Cl − -fluxes should be considered as a relevant factor of short term plasticity. Author Summary Information processing in the brain requires that excitation and inhibition are balanced. The main inhibitory neurotransmitter in the brain is gamma-amino-butyric acid (GABA). GABA actions depend on the Cl − -gradient, but activation of ionotropic GABA receptors causes Cl − -fluxes and thus reduces GABAergic inhibition. Here, we investigated how a coincident membrane depolarization by excitatory, glutamatergic synapses influences GABA-induced Cl − -fluxes using a biophysical compartmental model of Cl − dynamics, simulating either simple or realistic neuron topologies. We demonstrate that glutamatergic co-stimulation directly affects GABA-induced Cl − -fluxes, with the size of glutamatergic effects depending on the conductance, the decay kinetics, and localization of glutamatergic inputs. We also show that the glutamatergic shift in GABAergic Cl − -fluxes is surprisingly stable over a substantial range of latencies between glutamatergic and GABAergic inputs. We conclude from these results that glutamatergic co-stimulation alters GABAergic Cl − -fluxes and in turn affects the strength of GABAergic inhibition. These coincidence-dependent ionic changes should be considered as a relevant factor of short term plasticity in the CNS.
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The current study investigates the neurotrophic effects of Clostridium botulinum C3 transferase (C3bot) on highly purified, glia-free, GABAergic, and glutamatergic neurons. Incubation with nanomolar concentrations of C3bot promotes dendrite formation as well as dendritic and axonal outgrowth in rat GABAergic neurons. A comparison of C3bot effects on sorted mouse GABAergic and glutamatergic neurons obtained from newly established NexCre;Ai9xVGAT Venus mice revealed a higher sensitivity of GABAergic cells to axonotrophic and dendritic effects of C3bot in terms of process length and branch formation. Protein biochemical analysis of known C3bot binding partners revealed comparable amounts of β1 integrin in both cell types but a higher expression of vimentin in GABAergic neurons. Accordingly, binding of C3bot to GABAergic neurons was stronger than binding to glutamatergic neurons. A combinatory treatment of glutamatergic neurons with C3bot and vimentin raised the amount of bound C3bot to levels comparable to the ones in GABAergic neurons, thereby confirming the specificity of effects. Overall, different surface vimentin levels between GABAergic and glutamatergic neurons exist that mediate neurotrophic C3bot effects.
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Abstract We have studied γ‐aminobutyric acid (GABA) A receptor (GABA A R) clustering within the axon initial segment (AIS) in low‐density cultures of hippocampal pyramidal cells following GABAergic and glutamatergic innervation of the AIS. Large, intensely fluorescent, and postsynaptic GABA A R clusters were present in the AIS. More than 95% of these clusters colocalized with presynaptic GABAergic or glutamatergic terminals, forming matched or mismatched synapses, respectively. Less than 5% of the GABA A R clusters of the AIS did not colocalize with GABAergic or glutamatergic terminals, suggesting that GABA A Rs normally do not form clusters unless the AIS received GABAergic or glutamatergic innervation. Few or no clusters of the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐propionate (AMPA) receptors or the postsynaptic density‐95 protein (PSD‐95) were found in the AIS, even when the AIS was innervated by glutamatergic axons. Glutamatergic innervation of the AIS that formed mismatched synapses with postsynaptic GABA A R clusters mainly occurred when the AIS did not receive GABAergic innervation. However, when the AIS was innervated by GABAergic axons, the formation of matched GABAergic synapses predominated and coincided with large reductions in both the density of glutamatergic terminals from the AIS and the mismatching of GABA A R clusters. A similar effect was observed at axo‐dendritic synapses, where GABAergic innervation also led to a large decrease in mismatched GABA A R clusters and a smaller, but significant, decrease in glutamatergic terminal density in dendrites that received GABAergic innervation. We hypothesize that competition between GABAergic and glutamatergic innervation of the AIS in the intact hippocampus leads to the exclusive presence of GABAergic inhibitory synapses in the AIS of pyramidal cells. J. Comp. Neurol. 456:361–374, 2003. © 2003 Wiley‐Liss, Inc.
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The impact of GABAergic transmission on neuronal excitability depends on the Cl - -gradient across membranes. However, the Cl - -fluxes through GABA A receptors alter the intracellular Cl - concentration ([Cl - ] i ) and in turn attenuate GABAergic responses, a process termed ionic plasticity. Recently it has been shown that coincident glutamatergic inputs significantly affect ionic plasticity. Yet how the [Cl - ] i changes depend on the properties of glutamatergic inputs and their spatiotemporal relation to GABAergic stimuli is unknown. To investigate this issue, we used compartmental biophysical models of Cl - dynamics simulating either a simple ball-and-stick topology or a reconstructed CA3 neuron. These computational experiments demonstrated that glutamatergic co-stimulation enhances GABA receptor-mediated Cl - influx at low and attenuates or reverses the Cl - efflux at high initial [Cl - ] i . The size of glutamatergic influence on GABAergic Cl - -fluxes depends on the conductance, decay kinetics, and localization of glutamatergic inputs. Surprisingly, the glutamatergic shift in GABAergic Cl - -fluxes is invariant to latencies between GABAergic and glutamatergic inputs over a substantial interval. In agreement with experimental data, simulations in a reconstructed CA3 pyramidal neuron with physiological patterns of correlated activity revealed that coincident glutamatergic synaptic inputs contribute significantly to the activity-dependent [Cl - ] i changes. Whereas the influence of spatial correlation between distributed glutamatergic and GABAergic inputs was negligible, their temporal correlation played a significant role. In summary, our results demonstrate that glutamatergic co-stimulation had a substantial impact on ionic plasticity of GABAergic responses, enhancing the attenuation of GABAergic inhibition in the mature nervous systems, but suppressing GABAergic [Cl - ] i changes in the immature brain. Therefore, glutamatergic shift in GABAergic Cl - -fluxes should be considered as a relevant factor of short-term plasticity.
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Acidosis impairs brain functions. Neuron-specific mechanisms underlying acidosis-induced brain dysfunction remain elusive. We studied the sensitivity of cortical GABAergic neurons and glutamatergic neurons to acidosis by whole-cell recording in brain slices. The acidification to the neurons was induced by perfusing artificial cerebral spinal fluid with lower pH. This acidification impairs excitability and synaptic transmission in the glutamatergic and GABAergic neurons. Acidosis impairs spiking capacity in the GABAergic neurons more than in the glutamatergic neurons. Acidosis also strengthens glutamatergic synaptic transmission and attenuates GABAergic synaptic transmission on the GABAergic neurons more than the glutamatergic neurons, which results in the functional impairment of these GABAergic neurons. This acidosis-induced dysfunction predominantly in the cortical GABAergic neurons drives the homeostasis of neuronal networks toward overexcitation and exacerbates neuronal impairment.
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