The excitability of dorsal horn neurons is affected by cerebrospinal fluid from humans with osteoarthritis

2012 ◽  
Vol 90 (6) ◽  
pp. 783-790
Author(s):  
Van B. Lu ◽  
Peter A. Smith ◽  
Saifee Rashiq
Keyword(s):  
Synaptic Transmission ◽  
Dorsal Horn ◽  
Sensory Processing ◽  
Human Subjects ◽  
Substantia Gelatinosa ◽  
Inhibitory Neurons ◽  
Membrane Properties ◽  
Electrophysiological Properties ◽  
Osteoarthritis Pain ◽  
Cultured Slices

Changes in central neural processing are thought to contribute to the development of chronic osteoarthritis pain. This may be reflected as the presence of inflammatory mediators in the cerebral spinal fluid (CSF). We therefore exposed organotypically cultured slices of rat spinal cord to CSF from human subjects with osteoarthritis (OACSF) at a ratio of 1 part CSF in 9 parts culture medium for 5–6 days, and measured changes in neuronal electrophysiological properties by means of whole-cell recording. Although OACSF had no effect on the membrane properties and excitability of neurons in the substantia gelatinosa, synaptic transmission was clearly altered. The frequency of spontaneous excitatory postsynaptic currents (sEPSC) in delay-firing putative excitatory neurons was increased, as was sEPSC amplitude and frequency in tonic-firing inhibitory neurons. These changes could affect sensory processing in the dorsal horn, and may affect the transfer of nociceptive information. Although OACSF also affected inhibitory synaptic transmission (frequency of spontaneous inhibitory synaptic currents; sIPSC), this may have little bearing on sensory processing by substantia gelatinosa neurons, as sEPSC frequency is >3× greater than sIPSC frequency in this predominantly excitatory network. These results support the clinical notion that changes in nociceptive processing at the spinal level contribute to the generation of chronic osteoarthritis pain.

Long-term actions of BDNF on inhibitory synaptic transmission in identified neurons of the rat substantia gelatinosa

2012 ◽  
Vol 108 (2) ◽  
pp. 441-452 ◽  
Author(s):  
Van B. Lu ◽  
William F. Colmers ◽  
Peter A. Smith
Keyword(s):  
Synaptic Transmission ◽  
Peripheral Nerve ◽  
Dorsal Horn ◽  
Nerve Injury ◽  
Peripheral Nerve Injury ◽  
Substantia Gelatinosa ◽  
Inhibitory Neurons ◽  
Acid Decarboxylase ◽  
Spinal Cord Neurons ◽  
Excitatory Neurons

Peripheral nerve injury promotes the release of brain-derived neurotrophic factor (BDNF) from spinal microglial cells and primary afferent terminals. This induces an increase in dorsal horn excitability that contributes to “central sensitization” and to the onset of neuropathic pain. Although it is accepted that impairment of GABAergic and/or glycinergic inhibition contributes to this process, certain lines of evidence suggest that GABA release in the dorsal horn may increase after nerve injury. To resolve these contradictory findings, we exposed rat spinal cord neurons in defined-medium organotypic culture to 200 ng/ml BDNF for 6 days to mimic the change in spinal BDNF levels that accompanies peripheral nerve injury. Morphological and electrophysiological criteria and glutamic acid decarboxylase (GAD) immunohistochemistry were used to distinguish putative inhibitory tonic-islet-central neurons from putative excitatory delay-radial neurons. Whole cell recording in the presence of 1 μM tetrodotoxin showed that BDNF increased the amplitude of GABAergic and glycinergic miniature inhibitory postsynaptic currents (mIPSCs) in both cell types. It also increased the amplitude and frequency of spontaneous, action potential-dependent IPSCs (sIPSCs) in putative excitatory neurons. By contrast, BDNF reduced sIPSC amplitude in inhibitory neurons but frequency was unchanged. This increase in inhibitory drive to excitatory neurons and decreased inhibitory drive to inhibitory neurons seems inconsistent with the observation that BDNF increases overall dorsal horn excitability. One of several explanations for this discrepancy is that the action of BDNF in the substantia gelatinosa is dominated by previously documented increases in excitatory synaptic transmission rather than by impediment of inhibitory transmission.

scholarly journals Electrophysiological Properties of Substantia Gelatinosa Neurons in the Preparation of a Slice of Middle-Aged Rat Spinal Cord

2021 ◽  
Vol 13 ◽  
Author(s):  
Yang Li ◽  
Shanchu Su ◽  
Jiaqi Yu ◽  
Minjing Peng ◽  
Shengjun Wan ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Patch Clamp ◽  
Molecular Mechanisms ◽  
Substantia Gelatinosa ◽  
Membrane Properties ◽  
Middle Aged ◽  
Patch Clamp Recording ◽  
Electrophysiological Properties ◽  
Glutamatergic Neurons ◽  
Single Spike

A patch-clamp recording in slices generated from the brain or the spinal cord has facilitated the exploration of neuronal circuits and the molecular mechanisms underlying neurological disorders. However, the rodents that are used to generate the spinal cord slices in previous studies involving a patch-clamp recording have been limited to those in the juvenile or adolescent stage. Here, we applied an N-methyl-D-glucamine HCl (NMDG-HCl) solution that enabled the patch-clamp recordings to be performed on the superficial dorsal horn neurons in the slices derived from middle-aged rats. The success rate of stable recordings from substantia gelatinosa (SG) neurons was 34.6% (90/260). When stimulated with long current pulses, 43.3% (39/90) of the neurons presented a tonic-firing pattern, which was considered to represent γ-aminobutyric acid-ergic (GABAergic) signals. Presumptive glutamatergic neurons presented 38.9% (35/90) delayed and 8.3% (7/90) single-spike patterns. The intrinsic membrane properties of both the neuron types were similar but delayed (glutamatergic) neurons appeared to be more excitable as indicated by the decreased latency and rheobase values of the action potential compared with those of tonic (GABAergic) neurons. Furthermore, the glutamatergic neurons were integrated, which receive more excitatory synaptic transmission. We demonstrated that the NMDG-HCl cutting solution could be used to prepare the spinal cord slices of middle-aged rodents for the patch-clamp recording. In combination with other techniques, this preparation method might permit the further study of the functions of the spinal cord in the pathological processes that occur in aging-associated diseases.

Sciatic Chronic Constriction Injury Produces Cell-Type-Specific Changes in the Electrophysiological Properties of Rat Substantia Gelatinosa Neurons

2006 ◽  
Vol 96 (2) ◽  
pp. 579-590 ◽  
Author(s):  
Sridhar Balasubramanyan ◽  
Patrick L. Stemkowski ◽  
Martin J. Stebbing ◽  
Peter A. Smith
Keyword(s):  
Action Potential ◽  
Dorsal Horn ◽  
Chronic Constriction Injury ◽  
Input Resistance ◽  
Substantia Gelatinosa ◽  
Resting Membrane Potential ◽  
Cellular Mechanisms ◽  
Electrophysiological Properties ◽  
Putative Role ◽  
Cell Recording

Peripheral nerve injury increases spontaneous action potential discharge in spinal dorsal horn neurons and augments their response to peripheral stimulation. This “central hypersensitivity, ” which relates to the onset and persistence of neuropathic pain, reflects spontaneous activity in primary afferent fibers as well as long-term changes in the intrinsic properties of the dorsal horn (centralization). To isolate and investigate cellular mechanisms underlying “centralization,” sciatic nerves of 20-day-old rats were subjected to 13–25 days of chronic constriction injury (CCI; Mosconi-Kruger polyethylene cuff model). Spinal cord slices were then acutely prepared from sham-operated or CCI animals, and whole cell recording was used to compare the properties of five types of substantia gelatinosa neuron. These were defined as tonic, irregular, phasic, transient, or delay according to their discharge pattern in response to depolarizing current. CCI did not affect resting membrane potential, rheobase, or input resistance in any neuron type but increased the amplitude and frequency of spontaneous and miniature excitatory postsynaptic currents (EPSCs) in delay, transient, and irregular cells. These changes involved alterations in the action potential-independent neurotransmitter release machinery and possible increases in the postsynaptic effectiveness of glutamate. By contrast, in tonic cells, CCI reduced the amplitude and frequency of spontaneous and miniature EPSCs. Such changes may relate to the putative role of tonic cells as inhibitory GABAergic interneurons, whereas increased synaptic drive to delay cells may relate to their putative role as the excitatory output neurons of the substantia gelatinosa. Complementary changes in synaptic excitation of inhibitory and excitatory neurons may thus contribute to pain centralization.

scholarly journals Interplay of BDNF and GDNF in the mature spinal somatosensory system and its potential therapeutic relevance

2020 ◽  
Vol 18 ◽  
Author(s):  
Francesco Ferrini ◽  
Chiara Salio ◽  
Elena Boggio ◽  
Adalberto Merighi
Keyword(s):  
Synaptic Transmission ◽  
Dorsal Horn ◽  
Somatosensory System ◽  
Inhibitory Neurons ◽  
Equilibrium Potential ◽  
Superficial Dorsal Horn ◽  
Nociceptive Transmission ◽  
Two Factors ◽  
Pathological Pain

: The growth factors BDNF and GDNF are gaining more and more attention as modulators of synaptic transmission in the mature central nervous system (CNS). The two molecules undergo a regulated secretion in neurons and may be anterogradely transported to terminals where they can positively or negatively modulate fast synaptic transmission. There is today wide consensus on the role of BDNF as a pro-nociceptive modulator, as the neurotrophin has an important part in the initiation and maintenance of inflammatory, chronic, and/or neuropathic pain at peripheral and central level. At spinal level, BDNF intervenes in the regulation of chloride equilibrium potential, decreases the excitatory synaptic drive to inhibitory neurons, with complex changes in GABAergic/glycinergic synaptic transmission, and increases excitatory transmission in the superficial dorsal horn. Differently from BDNF, the role of GDNF still remains to be unraveled in full. This review resumes the current literature on the interplay between BDNF and GDNF in the regulation of nociceptive neurotransmission in the superficial dorsal horn of the spinal cord. We will first discuss the circuitries involved in such a regulation, as well as the reciprocal interactions between the two factors in nociceptive pathways. The development of small molecules specifically targeting BDNF, GDNF and/or downstream effectors is opening new perspectives for investigating these neurotrophic factors as modulations of nociceptive transmission and chronic pain. Therefore, we finally will consider the molecules of (potential) pharmacological relevance for tackling normal and pathological pain.

Developmental Changes in Electrophysiological Properties and Synaptic Transmission in Rat Intracardiac Ganglion Neurons

2006 ◽  
Vol 95 (6) ◽  
pp. 3543-3552 ◽  
Author(s):  
Katrina Rimmer ◽  
Alexander A. Harper
Keyword(s):  
Synaptic Transmission ◽  
Postnatal Development ◽  
Input Resistance ◽  
Membrane Resistance ◽  
Membrane Properties ◽  
Right Atrial ◽  
Electrophysiological Properties ◽  
Ganglion Neurons ◽  
Somatic Action Potentials ◽  
Parasympathetic Regulation

We charted postnatal changes in the intrinsic electrophysiological properties and synaptic responses of rat intrinsic cardiac ganglion (ICG) neurons. We developed a whole-mount ganglion preparation of the excised right atrial ganglion plexus. Using intracellular recordings and nerve stimulation we tested the hypothesis that substantial transformations in the intrinsic electrical characteristics and synaptic transmission accompany postnatal development. Membrane potential ( Em) did not change but time constant (τ) and cell capacitance increased with postnatal development. Accordingly, input resistance ( Rin) decreased but specific membrane resistance ( Rm) increased postnatally. Comparison of the somatic active membrane properties revealed significant changes in electrical phenotype. All neonatal neurons had somatic action potentials (APs) with small overshoots and small afterhyperpolarizations (AHPs). Adult neurons had somatic APs with large overshoots and large AHP amplitudes. The range of AHP duration was larger in adults than in neonates. The AP characteristics of juvenile neurons resembled those of adults, with the exception of AHP duration, which fell midway between neonate and adult values. Phasic, multiply adapting, and tonic evoked discharge activities were recorded from ICG neurons. Most neurons displayed phasic discharge at each developmental stage. All neurons received excitatory synaptic inputs from the vagus or interganglionic nerve trunk(s), the strength of which did not change significantly with postnatal age. The changes in the electrophysiological properties of the postganglionic neuron suggest that increased complexity of parasympathetic regulation of cardiac function accompanies postnatal development.

Modulation of synaptic transmission from primary afferents to spinal substantia gelatinosa neurons by group III mGluRs in GAD65-EGFP transgenic mice

2011 ◽  
Vol 105 (3) ◽  
pp. 1102-1111 ◽  
Author(s):  
Lian Cui ◽  
Yoo Rim Kim ◽  
Hye Young Kim ◽  
Seok Chan Lee ◽  
Hee-Sup Shin ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Action Potential ◽  
Synaptic Transmission ◽  
Dorsal Horn ◽  
Firing Pattern ◽  
Primary Afferents ◽  
Substantia Gelatinosa ◽  
Primary Afferent ◽  
Group Iii ◽  
Physiological Properties

Group III metabotropic glutamate receptors (mGluRs) are involved in nociceptive transmission in the spinal cord. However, the cellular mechanism underlying the modulation of synaptic transmission from nociceptive primary afferents to dorsal horn neurons by group III mGluRs has yet to be explored. In this study, we used transgenic mice expressing enhanced green fluorescent protein (EGFP) under the control of the glutamate decarboxylase (GAD) 65 promoter to identify specific subpopulations of GABAergic inhibitory interneurons. By GABA immunolabeling, we confirmed the majority of GAD65-EGFP-expressing neurons were GABAergic. Because GAD65-EGFP-expressing neurons have not been examined in detail before, we first investigated the physiological properties of GAD65-EGFP- and non-EGFP-expressing neurons in substantia gelatinosa (SG) of the spinal dorsal horn. Membrane properties, such as the resting membrane potential, membrane capacitance, action potential threshold, and action potential height, differed significantly between these two groups of neurons. Most EGFP-expressing neurons displayed a tonic firing pattern (73% of recorded neurons) and received monosynaptic Aδ and/or C primary afferent inputs (85% of recorded neurons). In contrast, we observed a delayed firing pattern in 53% of non-EGFP-expressing neurons. After identifying the physiological properties of EGFP-expressing neurons, we tested the effects of group III mGluRs on synaptic transmission pharmacologically. A group III mGluR agonist, L-AP4, attenuated Aδ fiber-evoked synaptic transmission but did not affect C fiber-evoked synaptic transmission to EGFP-expressing neurons. Similar primary afferent-specific inhibition by L-AP4 was also observed in non-EGFP-expressing neurons. Moreover, Aδ fiber-evoked synaptic transmission was suppressed by a selective mGluR7 agonist, AMN082. These results suggest that modulation of the synaptic transmission from primary afferents to SG neurons by group III mGluR agonist is specific to the type of nociceptive primary afferents but not to the type of target neurons.

Effects of Sciatic Nerve Axotomy on Excitatory Synaptic Transmission in Rat Substantia Gelatinosa

2009 ◽  
Vol 102 (6) ◽  
pp. 3203-3215 ◽  
Author(s):  
Yishen Chen ◽  
Sridhar Balasubramanyan ◽  
Aaron Y. Lai ◽  
Kathryn G. Todd ◽  
Peter A. Smith
Keyword(s):  
Sciatic Nerve ◽  
Spontaneous Activity ◽  
Dorsal Horn ◽  
Substantia Gelatinosa ◽  
Inhibitory Neurons ◽  
Resting Membrane Potential ◽  
Afferent Neurons ◽  
Primary Afferent Neurons ◽  
Primary Afferent ◽  
Synaptic Excitation

Injury or section of a peripheral nerve can promote chronic neuropathic pain. This is initiated by the appearance and persistence of ectopic spontaneous activity in primary afferent neurons that promotes a secondary, enduring increase in excitability of sensory circuits in the spinal dorsal horn (“central sensitization”). We have previously shown that 10–20 days of chronic constriction injury (CCI) of rat sciatic nerve produce a characteristic “electrophysiological signature” or pattern of changes in synaptic excitation of five different electrophysiologically defined neuronal phenotypes in the substantia gelatinosa of the dorsal horn. Although axotomy and CCI send different signals to the dorsal horn, we now find, using whole cell recording, that the “electrophysiological signature” produced 12–22 days after sciatic axotomy is quite similar to that seen with CCI. Axotomy thus has little effect on resting membrane potential, rheobase, current–voltage characteristics, or excitability of most neuron types; however, it does decrease excitatory synaptic drive to tonic firing neurons, while increasing that to delay firing neurons. Since many tonic neurons are GABAergic, whereas delay neurons do not contain γ-aminobutyric acid, axotomy may reduce synaptic excitation of inhibitory neurons while increasing that of excitatory neurons. Further analysis of spontaneous and miniature (tetrodotoxin-resistant) excitatory postsynaptic currents is consistent with the possibility that decreased excitation of tonic neurons reflects loss of presynaptic contacts. By contrast, increased excitation of “delay” neurons may reflect increased frequency of discharge of presynaptic action potentials. This would explain how synaptic excitation of tonic cells decreases despite the fact that axotomy increases spontaneous activity in primary afferent neurons.

scholarly journals Neuron-specific spinal cord translatomes reveal a neuropeptide code for mouse dorsal horn excitatory neurons

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rebecca Rani Das Gupta ◽  
Louis Scheurer ◽  
Pawel Pelczar ◽  
Hendrik Wildner ◽  
Hanns Ulrich Zeilhofer
Keyword(s):  
Spinal Cord ◽  
Dorsal Horn ◽  
Functional Organization ◽  
Affinity Purification ◽  
Expression Patterns ◽  
Inhibitory Neurons ◽  
Dorsal Horn Neurons ◽  
Expression Of Genes ◽  
Excitatory Neurons ◽  
Genes Encoding

AbstractThe spinal dorsal horn harbors a sophisticated and heterogeneous network of excitatory and inhibitory neurons that process peripheral signals encoding different sensory modalities. Although it has long been recognized that this network is crucial both for the separation and the integration of sensory signals of different modalities, a systematic unbiased approach to the use of specific neuromodulatory systems is still missing. Here, we have used the translating ribosome affinity purification (TRAP) technique to map the translatomes of excitatory glutamatergic (vGluT2+) and inhibitory GABA and/or glycinergic (vGAT+ or Gad67+) neurons of the mouse spinal cord. Our analyses demonstrate that inhibitory and excitatory neurons are not only set apart, as expected, by the expression of genes related to the production, release or re-uptake of their principal neurotransmitters and by genes encoding for transcription factors, but also by a differential engagement of neuromodulator, especially neuropeptide, signaling pathways. Subsequent multiplex in situ hybridization revealed eleven neuropeptide genes that are strongly enriched in excitatory dorsal horn neurons and display largely non-overlapping expression patterns closely adhering to the laminar and presumably also functional organization of the spinal cord grey matter.

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