| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
REPORT
1Department of Anatomy and Developmental Biology, University College London, London, United Kingdom; and 2Department of Anesthesiology, University of Cincinnati, Cincinnati, Ohio
Submitted 12 December 2007; accepted in final form 8 April 2008
 |
ABSTRACT |
|---|
|
-aminobutyric acid (GABA) type A receptors augments neuronal firing in vivo from the first days of life. However, it is possible that more subtle deficits in GABAergic signaling exist in the neonate, such as decreased reliability of transmission or greater depression during repetitive stimulation, both of which could influence the relative excitability of the immature spinal cord. To address this issue we examined monosynaptic GABAergic inputs onto superficial dorsal horn neurons using whole cell patch-clamp recordings made in spinal cord slices at a range of postnatal ages (P3, P10, and P21). The amplitudes of evoked inhibitory postsynaptic currents (IPSCs) were significantly lower and showed greater variability in younger animals, suggesting a lower fidelity of GABAergic signaling at early postnatal ages. Paired-pulse ratios were similar throughout the postnatal period, whereas trains of stimuli (1, 5, 10, and 20 Hz) revealed frequency-dependent short-term depression (STD) of IPSCs at all ages. Although the magnitude of STD did not differ between ages, the recovery from depression was significantly slower at immature GABAergic synapses. These properties may affect the integration of synaptic inputs within developing superficial dorsal horn neurons and thus contribute to their larger receptive fields and enhanced afterdischarge. |
|
INTRODUCTION |
|---|
|
; Fitzgerald and Gibson 1984; Holmberg and Schouenborg 1996; Torsney and Fitzgerald 2002). Since the intrinsic excitability of superficial dorsal horn neurons remains stable during early postnatal development (Baccei and Fitzgerald 2005), we have hypothesized that the differences in cutaneous responsiveness in younger and older animals arise from immature inhibitory dorsal horn networks (Baccei and Fitzgerald 2006; Fitzgerald 2005). This idea is supported by the increase in frequency and amplitude of spontaneous and evoked inhibitory currents, respectively, over the postnatal period and the minimal endogenous glycinergic inhibition in the dorsal horn until the second week of life (Baccei and Fitzgerald 2004). As in other areas of the CNS (Akerman and Cline 2006; Ben Ari et al. 1989; Rivera et al. 1999), immature neurons in the dorsal horn can be depolarized rather than hyperpolarized by -aminobutyric acid type A receptor (GABAAR) activation due to elevated intracellular chloride levels (Baccei and Fitzgerald 2004). However, unlike the immature hippocampus, where there is a prominent excitatory GABAergic drive, GABAAR-mediated depolarizations do not reach action potential threshold in the neonatal dorsal horn in vitro (Baccei and Fitzgerald 2004). These depolarizations may still have facilitatory effects but they will be limited by the temporal and spatial organization of other inputs in the network (Gulledge and Stuart 2003; Jean-Xavier et al. 2007). When examined in vivo, GABAAR-mediated baseline activity is clearly inhibitory from birth, as shown by the increase in dorsal horn activity and decreased reflex thresholds following neonatal spinal application of GABAAR antagonists (Bremner et al. 2006; Hathway et al. 2006). Although a simple developmental switch in GABAergic function is an unlikely explanation for the baseline cutaneous excitability in the immature spinal cord, the reduced chloride extrusion capacity of immature neurons may lead to Cl– accumulation during high-frequency trains of stimuli. This may cause a transient reversal in the direction of the chloride current, thus compromising the strength of GABAergic inhibition in young animals when faced with prolonged or intense stimulation (Cordero-Erausquin et al. 2005).
Alterations in the strength of dorsal horn GABAergic synapses during repetitive stimulation are likely to depend on presynaptic factors (Jensen et al. 1999a,1999b; Kirischuk et al. 2002) as well as postsynaptic mechanisms such as intracellular chloride accumulation. However, to date no studies have examined the functional properties of short-term plasticity at GABAergic synapses in the developing dorsal horn under experimental conditions that minimize any shift in postsynaptic chloride levels during repetitive stimulation. In addition, although a lower fidelity of transmitter release has been reported for excitatory synapses in the immature brain stem (Chuhma and Ohmori 1998), it is still unknown whether the reliability of GABAAR-mediated inhibition is lower in the neonatal dorsal horn, which could lead to greater fluctuations in inhibitory efficacy at early postnatal ages.
The present study demonstrates for the first time that immature GABAergic synapses in the dorsal horn exhibit a lower fidelity of transmission and slower recovery from short-term depression (STD) following repetitive activation, which are likely to hinder the consistency of inhibitory control in the neonatal spinal cord.
|
|
METHODS |
|---|
|
All experiments were conducted in accordance with the United Kingdom Animals (Scientific Procedures) Act of 1986. Neonatal Sprague–Dawley pups (P3–P21) were anesthetized with sodium pentobarbital (30 mg/kg, administered intraperitoneally) and then perfused transcardially with ice-cold dissection solution consisting of (in mM): 250 sucrose, 2.5 KCl, 25 NaHCO3, 1.0 NaH2PO4, 6 MgCl2, 0.5 CaCl2, and 25 glucose, which had been continuously bubbled with 95% O2-5% CO2. Following perfusion the vertebral column was rapidly removed and placed in a bath filled with dissection solution. The lumbar spinal cord was isolated and immersed in low-melting-point agarose (3% in above solution; GibcoBRL, Paisley, UK) and parasagittal slices (350–400 µm) were cut using a Vibroslice tissue slicer (HA-752; Campden Instruments; Leicester, UK). The slices were placed in a chamber filled with oxygenated dissection solution for 30 min then allowed to recover for a minimum of 1 h at room temperature in an oxygenated artificial cerebrospinal fluid (aCSF) solution containing (in mM): 125 NaCl, 2.5 KCl, 25 NaHCO3, 1.0 NaH2PO4, 1.0 MgCl2, 2.0 CaCl2, and 25 glucose.
Spinal cords were transferred to a submersion-type recording chamber (RC-22; Warner Instruments) and mounted on the stage of an upright microscope (Zeiss Axioskop 2; Welwyn Garden City, UK). Dorsal horn neurons were visualized with infrared differential interference contrast, and whole cell patch-clamp recordings were obtained as described previously (Baccei and Fitzgerald 2004). The tissue was continually perfused at room temperature with oxygenated aCSF solution at a rate of 1–3 ml/min. Glass pipette microelectrodes, with a resistance of 5–7 M
, were filled with a solution consisting of (in mM): 130 CsCl, 2.0 MgCl2, 10 HEPES, 2.0 Na2ATP, 0.4 Na3GTP, at pH 7.2 (270 mOsm). The local anesthetic agent N-(2,6-dimethylphenyl carbamoylmethyl)triethylammonium bromide (QX-314, 5 mM) was added to the pipette solution to block sodium channels. Synaptic responses were evoked extracellularly from a holding potential of –70 mV with a glass pipette microelectrode placed nearby in the superficial dorsal horn (50–100 µm from the recorded cell). The electrode was filled with aCSF solution and connected via silver wire to a constant-current stimulator (NeuroLog system; Digitimer, Hertfordshire, UK) controlled via a PC running Clampex software (Axon Instruments, Union City, CA). Monosynaptic GABAergic inhibitory postsynaptic currents (IPSCs) were pharmacologically isolated by bath application of antagonists to glycinergic and glutamatergic transmission [0.5 µM strychnine, 20 µM D-2-amino-5-phosphonopentanoic acid (D-AP5), and 10 µM 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX)].
Off-line analysis of IPSC amplitudes was conducted using Clampfit software (Axon Instruments). The coefficient of variation in IPSC amplitudes was calculated as the ratio of the SD to the mean (
40 trials per cell). To correct for spurious facilitation caused by random amplitude fluctuation (Kim and Alger 2001), paired-pulse ratios were calculated as: mean IPSC2/mean IPSC1 taken from four pairs of stimuli per cell at each interstimulus interval. To evaluate the extent of short-term depression (STD) during a train of 40 stimuli at various frequencies (1, 5, 10, and 20 Hz), we calculated a mean plateau amplitude (MPA) as: mean y/mean x, where y is the mean amplitude of the final five IPSCs and x is the amplitude of the first IPSC. To examine the recovery from STD, a train of 40 stimuli was applied at 20 Hz followed at various intervals (1–8 s) by a test stimulus of the same intensity. Recovery was calculated as: (mean z – mean y)/(mean x – mean y), where z is the amplitude of the response to the test stimulus and x and y are as described earlier.
Data are expressed as means ± SE and were tested for statistical significance (set at P < 0.05) using two-way repeated-measures (RM) ANOVA unless otherwise stated.
|
|
RESULTS |
|---|
|
Monosynaptic GABAAR-mediated IPSCs are smaller and more variable in immature dorsal horn neurons
To minimize changes in ECl during repetitive stimulation, we used an intracellular solution with a cesium chloride base. Under these conditions (in the presence of antagonists to glutamatergic and glycinergic transmission), monosynaptic GABAAR-mediated IPSCs appeared as inward currents from a holding potential of –70 mV and exhibited a reversal potential of about 0 mV (Fig. 1, A and B). These currents were abolished by the addition of the selective GABAAR antagonist gabazine (10 µM), confirming that they were GABAergic in origin (Fig. 1C).
|
= 63.6 ± 2.4 ms, n = 10; P10: = 57.7 ± 1.45 ms, n = 10; P21: = 56.7 ± 2.0 ms, n = 10; one-way ANOVA, P = 0.55). For each cell the coefficient of variation (CV) of IPSC amplitude was calculated as an absolute value and the mean of these values was compared across age groups (Fig. 1, D and F). A significant developmental decrease in the CV of IPSCs was seen between 3 and 21 days after birth (P3 = 0.47 ± 0.04, n = 11; P10 = 0.42 ± 0.06, n = 11; P21 = 0.30 ± 0.03, n = 10; one-way ANOVA with post hoc Tukey test, P < 0.05). Paired-pulse ratios of IPSCs are similar at all postnatal ages
To establish whether the efficacy of GABAergic synapses altered during repetitive activation and whether this was affected by postnatal age, we first examined the effect of paired-pulse stimulation on IPSC amplitude. A variety of interstimulus intervals (25 ms to 5 s) were applied and the resulting ratios (mean IPSC2/mean IPSC1) were compared between age groups. Moderate paired-pulse facilitation was observed at all ages and there was no significant difference in the paired-pulse ratio (PPR) observed at an interstimulus interval (ISI) of 100 ms (Fig. 2, A and B; P3, n = 28, P10, n = 28, P21, n = 30; one-way ANOVA, P = 0.48), or indeed at any other ISI examined (data not shown). To verify that the measured PPRs were determined by presynaptic factors, the effects of varying the external calcium concentration ([Ca]ext) were studied in a subset of neurons from P10 rats. As expected, reducing the probability of GABA release via a decrease in [Ca]ext from 2 to 0.8 mM led to a significant rise in PPR across a range of ISIs with an increase from 1.08 ± 0.1 to 3.08 ± 1.2 at 25 ms and from 1.23 ± 0.1 to 1.95 ± 0.6 at 50 ms (two-way ANOVA, P < 0.05; n = 6).
|
To examine the function of GABAergic synapses during prolonged stimulation, we applied trains of 40 focal stimuli at a range of frequencies (1, 5, 10, and 20 Hz). The stimulus intensity applied was twice threshold, except for that in a pilot run of three cells per age where 1.5-fold threshold was used. As a measure of short-term plasticity occurring during a given stimulus train, we calculated the MPA to reflect the average size of IPSCs at the end of the train compared with the first IPSC (Fig. 2C). Interestingly, significant frequency-dependent STD of IPSC amplitude was seen at all ages (P3, n = 11; P10, n = 11; P21, n = 10; P < 0.0001), and the extent of STD (as assessed by MPA) did not differ significantly between age groups (P = 0.85; Fig. 2, D and E) with a maximal reduction of about 70% seen at 20 Hz. The STD (measured during 10-Hz trains at P10) was found to be sensitive to [Ca]ext because lowering [Ca]ext from 2 to 0.8 mM significantly increased the MPA from 0.36 ± 0.09 to 1.13 ± 0.13 (P < 0.01, one-way ANOVA, n = 3). The abolition of STD by decreasing [Ca]ext demonstrates its sensitivity to changes in the probability of transmitter release and thus presynaptic origin. In addition, the first and last IPSCs in the train exhibited a similar ECl, suggesting that postsynaptic chloride homeostasis was maintained during the stimulation protocol (IPSC1 ECl = 8.6 ± 3.3 mV, IPSC40 ECl = 14.8 ± 3.1 mV; Student's t-test, P > 0.05, n = 4).
Finally, we investigated whether the rate at which immature GABAergic synapses recover from STD differed from their mature counterparts. A train of 40 stimuli at 20 Hz was applied followed 1 to 8 s later by a single test stimulus (Fig. 3 A) to measure recovery of IPSC amplitude (see METHODS for details). Postnatal age had a significant effect on the rate of recovery from depression (P3, n = 12; P10, n = 10; P21, n = 9; P < 0.05), with P3 neurons exhibiting a delayed recovery compared with those from P21 rats (Fig. 3B). The time required for IPSCs to recover to 50% of the baseline amplitude was 6.82 s at P3, 2.64 s at P10, and 0.84 s at P21.
|
|
|
DISCUSSION |
|---|
|
Postnatal development of spinal inhibitory circuits
Dorsal horn neurons in immature animals have larger cutaneous receptive fields and lower mechanical thresholds than those in older animals. In addition, repeated stimulation of cutaneous A fibers leads to increased activity and a prolonged afterdischarge, not observed in older animals (Jennings and Fitzgerald 1998). The consistency of the intrinsic membrane excitability of dorsal horn neurons across postnatal development suggests that these distinct firing properties arise from differences in circuit organization or function. One possibility is that inhibitory transmission is not yet mature in the first weeks of life. The local circuit interneurons of the substantia gelatinosa are born last (Altman and Bayer 1984; Bice and Beal 1997) and, unlike projection neurons, the maturation of their dendritic morphology occurs postnatally (Bicknell Jr and Beal 1984). One aspect of inhibitory control that appears immature in early postnatal life is the glycinergic system because only very weak glycine-receptor–mediated transmission is seen in lamina II in the first week after birth (Baccei and Fitzgerald 2004). This is in contrast to GABAARs, which are activated in the neonatal dorsal horn and are crucial in limiting the excitability of the immature spinal cord from birth (Bremner et al. 2006; Hathway et al. 2006). Although tonic GABAergic inhibition mediated by extrasynaptic GABAARs has been reported in many areas of the CNS, including the adult mouse dorsal horn (Ataka and Gu 2006), recent evidence has demonstrated that lamina II neurons in P15–P21 rats lack a persistent GABAAR-mediated conductance at physiological temperatures (Mitchell et al. 2007). Further studies are required to elucidate the precise contribution of extrasynaptic GABAARs to the overall inhibitory tone within the rat dorsal horn during early postnatal development.
Although GABAergic inhibition is present in early postnatal life, it may be less efficient than that in the adult. Previous reports have found that the magnitude of primary afferent-evoked GABAAR-mediated IPSCs in the dorsal horn increases over the first 2 wk (Baccei and Fitzgerald 2004). The present data suggest that this does not result solely from a postnatal strengthening of primary afferent synapses but also reflects an age-dependent increase in the efficacy of local inhibitory synapses within the superficial dorsal horn because the amplitude of focally evoked IPSCs increases over a similar developmental period. Other more subtle differences in the properties of synaptic transmission may also have important implications for signal integration within the superficial dorsal horn. Our data indicated that the fidelity of GABAergic synapses, which is inversely related to the CV of IPSC amplitude, was significantly lower in immature neurons than that in those from older animals. Because GABAAR activation is known to be involved in the restriction of receptive field size (Bremner et al. 2006), reduced and less reliable GABAergic transmission could contribute to the larger receptive fields seen in younger animals. The precise mechanisms underlying the age-dependent changes in the CV are not clear, although the lack of a postnatal change in the paired-pulse ratios (PPR) suggests that there is no significant change in the probability of GABA release over the age range studied. Since the CV of IPSC amplitudes is primarily determined by the number of active release sites and the release probability at these sites (Faber and Korn 1991), the decreased reliability of inhibition in immature neurons may therefore be the result of a lower number of active GABA release sites (Chuhma and Ohmori 1998). An age-dependent elevation in the number of GABA release sites could potentially explain both the observed developmental increase in the amplitude of focally evoked IPSCs (Fig. 1E) as well as previous reports that the frequency, but not amplitude, of GABAergic miniature (m)IPSCs increases during the early postnatal period (Baccei and Fitzgerald 2004).
Because extracellular stimulation was used in this study, it is possible that the observed developmental changes in the size and variability of IPSCs could instead be ascribed to differences in the response of GABAergic interneurons to electrical stimulation. This seems unlikely because the threshold for IPSC induction did not vary significantly across the three age groups studied. A previous study also identified no age-related changes in the membrane excitability of a mixed population of dorsal horn neurons (Baccei and Fitzgerald 2005), although we cannot completely discount the possibility that examining only GABAergic interneurons could have shown developmental changes in this parameter.
Functional implications of GABAergic short-term plasticity for spinal nociceptive processing
Repetitive stimulation of afferent inputs leads to increased excitability in the spinal cord (termed central sensitization), which may include long-term potentiation (LTP) of excitatory synapses onto lamina I projection neurons (Ikeda et al. 2003). These output cells of the superficial dorsal horn are under tight GABAergic control and removal of this inhibition unmasks new excitatory input that may contribute to spinal LTP (Torsney and MacDermott 2006). Thus GABAAR activation during conditioning trains may modulate the threshold for induction of LTP, as has been shown in other areas of the CNS (Grover and Yan 1999). Indeed, enhancing spinal GABAAR function in vivo by applying the benzodiazepine diazepam abolishes LTP of C-fiber–evoked field potentials in the dorsal horn (Hu et al. 2006). However, few studies to date have examined the properties of short-term plasticity at GABAergic synapses in the dorsal horn. The present results suggest that although short bursts of activity could lead to the potentiation of GABAAR transmission (as seen in paired-pulse experiments), prolonged activation of GABAergic synapses results in frequency-dependent STD that occurred with a similar magnitude at all postnatal ages studied. This depression of inhibitory strength can act as a low-pass filter on GABAergic signaling (Baimoukhametova et al. 2004), resulting in a reduction in the output of inhibitory neurons during periods of high-frequency firing, which may encourage activity-dependent plasticity such as LTP and central sensitization.
The time needed for GABAergic synapses to recover from STD creates an additional "window" of disinhibition during which GABAergic signaling will not function at full efficacy. This may facilitate excitatory postsynaptic potential summation and subsequent action potential discharge (Thompson et al. 1993) in the period following the initial stimulus, and may thus contribute to the afterdischarge observed in dorsal horn neurons in vivo. Since immature GABAergic synapses exhibited a significantly slower recovery from STD, this temporal window of reduced inhibition will be longer in the neonatal dorsal horn. During this window, any further activation of the synapse could lead to a cumulative decrease in GABAergic strength. As a result, the efficacy of immature GABAergic synapses may be progressively decreased during the repetitive stimulation of sensory inputs to the spinal cord. This could explain the previous observation that repetitive activation of primary afferents in vivo leads to a significant increase in the afterdischarge in neonatal dorsal horn neurons, which disappears by 21 days after birth (Jennings and Fitzgerald 1998).
The efficacy of GABAergic inhibition onto immature dorsal horn neurons during high-frequency stimulation may also be compromised by postsynaptic shifts in the chloride equilibrium potential (ECl), which can be caused by the reduced chloride extrusion capacity seen at early postnatal ages (Cordero-Erausquin et al. 2005). This mechanism does not underlie the STD seen in the present study because we used a high-chloride intracellular solution that maintained a stable ECl during the stimulus trains. Instead, the STD observed under our experimental conditions is likely to be presynaptically mediated, given that the magnitude of depression was significantly influenced by levels of extracellular calcium. Possible underlying mechanisms include depletion of the releasable pool of vesicles (Dobrunz and Stevens 1997), inactivation of calcium channels and/or the release machinery (Forsythe et al. 1998; Zucker and Regehr 2002), or the activation of presynaptic autoreceptors (Cui et al. 2000; Zucker and Regehr 2002). Overall, it appears that both pre- and postsynaptic factors can contribute to a reduction in the efficacy of GABAergic inhibition during prolonged and intense activity.
In conclusion, we have described a postnatal increase in both the strength and fidelity of GABAergic signaling in the superficial dorsal horn and the rate of recovery of inhibitory strength following repetitive stimulation. This result has important implications for the spatial and temporal processing of sensory information in young animals and may contribute to their enhanced responsiveness to cutaneous stimulation.
|
|
GRANTS |
|---|
|
|
|
FOOTNOTES |
|---|
Address for reprint requests and other correspondence: R. A. Ingram, University College London, Department of Anatomy and Developmental Biology, London, WC1E 6BT, UK (E-mail: rachel.ingram{at}ucl.ac.uk)
|
|
REFERENCES |
|---|
|
Altman J, Bayer SA. The development of the rat spinal cord. Adv Anat Embryol Cell Biol 85: 1–164, 1984.[Medline]
Ataka T, Gu JG. Relationship between tonic inhibitory currents and phasic inhibitory activity in the spinal cord lamina II region of adult mice. Mol Pain 2: 36–46, 2006.[CrossRef][Medline]
Baccei ML, Fitzgerald M. Development of GABAergic and glycinergic transmission in the neonatal rat dorsal horn. J Neurosci 24: 4749–4757, 2004.
Baccei ML, Fitzgerald M. Intrinsic firing properties of developing rat superficial dorsal horn neurons. Neuroreport 16: 1325–1328, 2005.[CrossRef][Web of Science][Medline]
Baccei ML, Fitzgerald M. Development of pain pathways and mechanisms. In: Textbook of Pain, edited by McMahon SB, Koltzenburg M. London: Elsevier, 2006, p. 143–158.
Baimoukhametova DV, Hewitt SA, Sank CA, Bains JS. Dopamine modulates use-dependent plasticity of inhibitory synapses. J Neurosci 24: 5162–5171, 2004.
Ben Ari Y, Cherubini E, Corradetti R, Gaiarsa JL. Giant synaptic potentials in immature rat CA3 hippocampal neurones. J Physiol 416: 303–325, 1989.
Bice TN, Beal JA. Quantitative and neurogenic analysis of the total population and subpopulations of neurons defined by axon projection in the superficial dorsal horn of the rat lumbar spinal cord. J Comp Neurol 388: 550–564, 1997.[CrossRef][Web of Science][Medline]
Bicknell HR Jr, Beal JA. Axonal and dendritic development of substantia gelatinosa neurons in the lumbosacral spinal cord of the rat. J Comp Neurol 226: 508–522, 1984.[CrossRef][Web of Science][Medline]
Bremner L, Fitzgerald M, Baccei M. Functional GABAA-receptor-mediated inhibition in the neonatal dorsal horn. J Neurophysiol 95: 3893–3897, 2006.
Chuhma N, Ohmori H. Postnatal development of phase-locked high-fidelity synaptic transmission in the medial nucleus of the trapezoid body of the rat. J Neurosci 18: 512–520, 1998.
Cordero-Erausquin M, Coull JAM, Boudreau D, Rolland M, Koninck YD. Differential maturation of GABA action and anion reversal potential in spinal lamina I neurons: impact of chloride extrusion capacity. J Neurosci 25: 9613–9623, 2005.
Cui LN, Coderre E, Renaud LP. GABAB presynaptically modulates suprachiasmatic input to hypothalamic paraventricular magnocellular neurons. Am J Physiol Regul Integr Comp Physiol 278: R1210–R1216, 2000.
Dobrunz LE, Stevens CF. Heterogeneity of release probability, facilitation, and depletion at central synapses. Neuron 18: 995–1008, 1997.[CrossRef][Web of Science][Medline]
Faber DS, Korn H. Applicability of the coefficient of variation method for analyzing synaptic plasticity. Biophys J 60: 1288–1294, 1991.[Web of Science][Medline]
Fitzgerald M. The post-natal development of cutaneous afferent fibre input and receptive field organization in the rat dorsal horn. J Physiol 364: 1–18, 1985.
Fitzgerald M. The development of nociceptive circuits. Nat Rev Neurosci 6: 507–520, 2005.[Web of Science][Medline]
Fitzgerald M, Gibson S. The postnatal physiological and neurochemical development of peripheral sensory C fibres. Neuroscience 13: 933–944, 1984.[CrossRef][Web of Science][Medline]
Forsythe ID, Tsujimoto T, Barnes-Davies M, Cuttle MF, Takahashi T. Inactivation of presynaptic calcium current contributes to synaptic depression at a fast central synapse. Neuron 20: 797–807, 1998.[CrossRef][Web of Science][Medline]
Grover LM, Yan C. Blockade of GABAA receptors facilitates induction of NMDA receptor-independent long-term potentiation. J Neurophysiol 81: 2814–2822, 1999.
Gulledge AT, Stuart GJ. Excitatory actions of GABA in the cortex. Neuron 37: 299–309, 2003.[CrossRef][Web of Science][Medline]
Hathway G, Harrop E, Baccei M, Walker S, Moss A, Fitzgerald M. A postnatal switch in GABAergic control of spinal cutaneous reflexes. Eur J Neurosci 23: 112–118, 2006.[CrossRef][Web of Science][Medline]
Holmberg H, Schouenborg J. Postnatal development of the nociceptive withdrawal reflexes in the rat: a behavioural and electromyographic study. J Physiol 493: 239–252, 1996.
Hu XD, Ge YX, Hu NW, Zhang HM, Zhou LJ, Zhang T, Li WM, Han YF, Liu XG. Diazepam inhibits the induction and maintenance of LTP of C-fiber evoked field potentials in spinal dorsal horn of rats. Neuropharmacology 50: 238–244, 2006.[CrossRef][Web of Science][Medline]
Ikeda H, Heinke B, Ruscheweyh R, Sandkuhler J. Synaptic plasticity in spinal lamina I projection neurons that mediate hyperalgesia. Science 299: 1237–1240, 2003.
Jean-Xavier C, Mentis GZ, O'Donovan MJ, Cattaert D, Vinay L. Dual personality of GABA/glycine-mediated depolarizations in immature spinal cord. Proc Natl Acad Sci USA 104: 11477–11482, 2007.
Jennings E, Fitzgerald M. Postnatal changes in responses of rat dorsal horn cells to afferent stimulation: a fibre-induced sensitization. J Physiol 509: 859–868, 1998.
Jensen K, Jensen MS, Lambert JDC. Post-tetanic potentiation of GABAergic IPSCs in cultured rat hippocampal neurones. J Physiol 519: 71–84, 1999a.
Jensen K, Lambert JDC, Jensen MS. Activity-dependent depression of GABAergic IPSCs in cultured hippocampal neurons. J Neurophysiol 82: 42–49, 1999b.
Kim J, Alger BE. Random response fluctuations lead to spurious paired-pulse facilitation. J Neurosci 21: 9608–9618, 2001.
Kirischuk S, Clements JD, Grantyn R. Presynaptic and postsynaptic mechanisms underlie paired pulse depression at single GABAergic boutons in rat collicular cultures. J Physiol 543: 99–116, 2002.
Mitchell EA, Gentet LJ, Dempster J, Belelli D. GABAA and glycine receptor-mediated transmission in rat lamina II neurones: relevance to the analgesic actions of neuroactive steroids. J Physiol 583: 1021–1040, 2007.
Rivera C, Voipio J, Payne JA, Ruusuvuori E, Lahtinen H, Lamsa K, Pirvola U, Saarma M, Kaila K. The K+/Cl– co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature 397: 251–255, 1999.[CrossRef][Medline]
Thompson SW, Woolf CJ, Sivilotti LG. Small-caliber afferent inputs produce a heterosynaptic facilitation of the synaptic responses evoked by primary afferent A-fibers in the neonatal rat spinal cord in vitro. J Neurophysiol 69: 2116–2128, 1993.
Torsney C, Fitzgerald M. Age-dependent effects of peripheral inflammation on the electrophysiological properties of neonatal rat dorsal horn neurons. J Neurophysiol 87: 1311–1317, 2002.
Torsney C, MacDermott AB. Disinhibition opens the gate to pathological pain signaling in superficial neurokinin 1 receptor-expressing neurons in rat spinal cord. J Neurosci 26: 1833–1843, 2006.
Zucker RS, Regehr WG. Short-term synaptic plasticity. Annu Rev Physiol 64: 355–405, 2002.[CrossRef][Web of Science][Medline]
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
TOP
ABSTRACT
INTRODUCTION
t), as shown in the example trace. B: plotting the normalized recovery as a function of