GABAergic synaptic transmission regulates calcium influx during spike-timing dependent plasticity (original) (raw)
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Long-term transformation of an inhibitory into an excitatory GABAergic synaptic response
Proceedings of the National Academy of Sciences, 1992
For a constant membrane potential, a predominantly inhibitory GABAergic synaptic response is shown to undergo long-term transformation into an excitatory response after pairing of exogenous gamma-aminobutyric acid (GABA) with postsynaptic depolarization or pairing of pre- and postsynaptic stimulation. Current- and voltage-clamp experiments suggest that this synaptic transformation is due to a shift from a net increase of conductance to a net decrease of conductance in response to GABA. GABA-induced elevation of intracellular calcium is prolonged after the same stimulus pairing and may, therefore, contribute to this synaptic transformation via Ca(2+)-activated phosphorylation pathways. This synaptic transformation, which does not follow unpaired stimulus presentations, occurs in a neuronal compartment spatially separated from the soma, which also changes during stimulus pairing.
GABAergic Circuits Control Spike-Timing-Dependent Plasticity
Journal of Neuroscience, 2013
The spike-timing-dependent plasticity (STDP), a synaptic learning rule for encoding learning and memory, relies on relative timing of neuronal activity on either side of the synapse. GABAergic signaling has been shown to control neuronal excitability and consequently the spike timing, but whether GABAergic circuits rule the STDP remained unknown. Here we show that GABAergic signaling governs the polarity of STDP, because blockade of GABA A receptors was able to completely reverse the temporal order of plasticity at corticostriatal synapses in rats and mice. GABA controls the polarity of STDP in both striatopallidal and striatonigral output neurons. Biophysical simulations and experimental investigations suggest that GABA controls STDP polarity through depolarizing effects at distal dendrites of striatal output neurons by modifying the balance of two calcium sources, NMDARs and voltage-sensitive calcium channels. These findings establish a central role for GABAergic circuits in shaping STDP and suggest that GABA could operate as a Hebbian/anti-Hebbian switch.
NeuroReport, 2009
Precisely controlled spike times relative to h-frequency network oscillations play an important role in hippocampal memory processing. Here we study how inhibitory synaptic input during h oscillation contributes to the control of spike timing. Using whole-cell patch-clamp recordings from CA1 pyramidal cells in vitro with dynamic clamp to simulate h-frequency oscillation (5 Hz), we show that c-aminobutyric acid-A (GABA A ) receptor-mediated inhibitory postsynaptic potentials (IPSPs) can not only delay but also advance the postsynaptic spike depending on the timing of the inhibition relative to the oscillation. Spike time advancement with IPSP was abolished by the h-channel blocker ZD7288 (10 lM), suggesting that IPSPs can interact with intrinsic membrane conductances to yield bidirectional control of spike timing.
Journal of Neurophysiology, 1997
Miura, Masami, Masatomo Yoshioka, Hiroyoshi Miyakawa, Hiroshi Kato, and Ken-Ichi Ito. Properties of calcium spikes revealed during GABAA receptor antagonism in hippocampal CA1 neurons from guinea pigs. J. Neurophysiol. 78: 2269–2279, 1997. Intracellular electrical responses and changes in intracellular calcium concentration ([Ca2+]i) in response to activation of synaptic inputs and to DC injections were recorded simultaneously from CA1 pyramidal neurons ( n = 42) in guinea pig hippocampal slices. In the presence of the γ-aminobutyric acid-A (GABAA) receptor antagonists, bicuculline (25 μM) and picrotoxin (10 μM), broad (>20 ms) all-or-none spikes were induced by activation of synaptic inputs (20 pulses, 30 Hz) and were accompanied by a simultaneous rapid and large rise in [Ca2+]i (34 of 34 cells). By contrast, direct depolarizing current (0.7 nA, 1 s) induced spikes having short duration, during which time the spike firing pattern was observed not to be significantly affected. Wh...
2010
Brickley SG, Cull-Candy SG, and Farrant M. Single-channel properties of synaptic and extrasynaptic GABA A receptors suggest differential targeting of receptor subtypes. J Neurosci 19: 2960 -2973, 1999. Brickley SG, Revilla V, Cull-Candy SG, Wisden W, and Farrant M. Adaptive regulation of neuronal excitability by a voltage-independent potassium conductance. Nature 409: 88 -92, 2001. Cavelier P, Hamann M, Rossi D, Mobbs P, and Attwell D. Tonic excitation and inhibition of neurons: ambient transmitter sources and computational consequences. Prog Biophys Mol Biol 87: 3-16, 2005. Cherubini E, Gaiarsa JL, and Ben-Ari Y. GABA: an excitatory transmitter in early postnatal life. Trends Neurosci 14: 515-519, 1991. Chiu CS, Brickley S, Jensen K, Southwell A, Mckinney S, Cull-Candy S, Mody I, and Lester HA. GABA transporter deficiency causes tremor, ataxia, nervousness, and increased GABA-induced tonic conductance in cerebellum. J Neurosci 25: 3234 -3245, 2005. Conti F, Minelli A, and Melone M. GABA transporters in the mammalian cerebral cortex: localization, development and pathological implications. Brain Res Brain Res Rev 45: 196 -212, 2004. Frahm C, Engel D, and Draguhn A. Efficacy of background GABA uptake in rat hippocampal slices. Neuroreport 12: 1593-1596, 2001. Gaspary HL, Wang W, and Richerson GB. Carrier-mediated GABA release activates GABA receptors on hippocampal neurons. J Neurophysiol 80: 270 -281, 1998. Hamann M, Rossi DJ, and Attwell D. Tonic and spillover inhibition of granule cells control information flow through cerebellar cortex. Neuron 33: 625-633, 2002. Hell JW, Edelmann L, Hartinger J, and Jahn R. Functional reconstitution of the ␥-aminobutyric acid transporter from synaptic vesicles using artificial ion gradients. Biochemistry 30: 11795-11800, 1991. Isaacson JS, Solis JM, and Nicoll RA. Local and diffuse synaptic actions of GABA in the hippocampus. Neuron 10: 165-175, 1993. Jensen K, Chiu CS, Sokolova I, Lester HA, and Mody I. GABA transporter-1 (GAT1)-deficient mice: differential tonic activation of GABA A versus GABA B receptors in the hippocampus. J Neurophysiol 90: 2690 -2701, 2003. Keros S and Hablitz JJ. Subtype-specific GABA transporter antagonists synergistically modulate phasic and tonic GABA A conductances in rat neocortex. J Neurophysiol 94: 2073-2085, 2005.
Cell, 2001
likely the result of an ontogenetic decrease in the intra-La Jolla, California 92093 cellular Cl Ϫ concentration ([Cl Ϫ ] i ; Cherubini et al., 1990; Luhmann and Prince, 1991; Chen et al., 1996; Owens et al., 1996). Indeed, changes in the mRNA level for the Summary K ϩ -coupled Cl Ϫ transporter KCC2 have been shown to correlate with the modification of GABAergic transmis-GABA is the main inhibitory neurotransmitter in the sion (Lu et al., 1999; Rivera et al., 1999; Vu et al., 2000). adult brain. Early in development, however, GABAergic KCC2 increases the rate of Cl Ϫ extrusion, thus leading synaptic transmission is excitatory and can exert to a reduction in [Cl Ϫ ] i and a consequent shift in E GABA widespread trophic effects. During the postnatal petoward more hyperpolarized potentials (Jarolimek et al., riod, GABAergic responses undergo a switch from be-1999; Kakazu et al., 1999; Rivera et al., 1999). ing excitatory to inhibitory. Here, we show that the This conversion of GABAergic transmission from deswitch is delayed by chronic blockade of GABA A receppolarizing to hyperpolarizing is also accompanied by a tors, and accelerated by increased GABA A receptor change in GABA-mediated biochemical signaling. Only activation. In contrast, blockade of glutamatergic during this early developmental period, depolarizing transmission or action potentials has no effect. Fur-GABAergic potentials activate voltage-dependent Ca 2ϩ thermore, GABAergic activity modulated the mRNA channels (VDCCs) and elevate [Ca 2ϩ ] i (Connor et al., levels of KCC2, a K ؉ -Cl Ϫ cotransporter whose expres-1987; Yuste and Katz, 1991; Wang et al., 1994). Such sion correlates with the switch. Finally, we report that GABA-induced elevation of [Ca 2ϩ ] i is likely to play a GABA can alter the properties of depolarizationcritical role in the maturation of the nervous system. induced Ca 2؉ influx. Thus, GABA acts as a self-limiting For instance, GABA-mediated increases in [Ca 2ϩ ] i can trophic factor during neural development. induce BDNF expression (Berninger et al., 1995) and promote neuronal survival and differentiation (LoTurco In the adult central nervous system, ␥-amino-butyric et al., 1995; Marty et al., 1996; Ikeda et al., 1997). GABAacid (GABA) is the primary inhibitory neurotransmitter. induced elevation of [Ca 2ϩ ] i may also be required to It regulates a neuron's ability to fire action potentials form, stabilize, and strengthen synaptic connections either through hyperpolarization of the membrane po-(Kirsch and Betz, 1998; Caillard et al., 1999; Kneussel tential or through shunting of excitatory inputs. During and Betz, 2000). early postnatal development, however, GABAergic syn-While the developmental transformation of GABAeraptic transmission is excitatory, able to elevate the intragic transmission is well documented, little is known cellular Ca 2ϩ concentration ([Ca 2ϩ ] i ), and even capable about signals that induce this transformation. Since neuof triggering action potentials (Mueller et al., 1984; Luhronal activity is known to increase during development, mann and Prince, 1991; Yuste and Katz, 1991; Reichling we examined in the present study whether synaptic acet al., 1994; Wang et al., 1994; Leinekugel et al., 1995; tivity can regulate the switch of GABAergic transmis-Obrietan and van den Pol, 1995; Chen et al., 1996; Owens sion. We found that the change in GABA signaling was et al., 1996; Khazipov et al., 1997). Over a limited postnalargely prevented by chronic blockade of GABA A receptal period, in the hippocampus, neocortex, and hypotors, and was accelerated by increased GABA receptor thalamus, as well as other regions of the brain, there is activation. Changes in the level of KCC2 mRNA tightly a switch of the electrophysiological (depolarization to correlated with the observed changes in GABA signalhyperpolarization) and biochemical (Ca 2ϩ -mediated siging. In addition, we found that spontaneous GABAergic naling) properties of GABAergic transmission (Mueller activity regulated the activation of voltage-dependent et al., 1984; Ben-Ari et al., 1989; Cherubini et al., 1991; Ca 2ϩ currents. These findings point to GABA as a critical Luhmann and Prince, 1991; Owens et al., 1996). maturation factor for the switch of the physiological and The GABA A receptor channel predominantly conducts biochemical properties of GABA signaling. Cl Ϫ ions. Consequently, the nature of GABAergic transmission, excitatory versus inhibitory, is determined pri-Results marily by the electrochemical gradient for Cl Ϫ , which depends on the intra-and extracellular concentrations Switch of GABAergic Transmission from Depolarizing of Cl Ϫ . This electrochemical gradient sets the reversal to Hyperpolarizing potential for GABAergic currents (E GABA ; the membrane To study the change in GABA signaling, we first monitored GABA-induced elevations of [Ca 2ϩ ] i over developchanges in fluorescence were measured using confocal Luhmann, H.J., and Prince, D.A. (1991). Postnatal maturation of the GABAergic system in rat neocortex. J. Neurophysiol. 65, 247-263. Marty, S., Berninger, B., Carroll, P., and Thoenen, H. (1996). GABAergic stimulation regulates the phenotype of hippocampal interneurons through the regulation of brain-derived neurotrophic factor. Neuron 16, 565-570. Mueller, A.L., Taube, J.S., and Schwartzkroin, P.A. (1984). Development of hyperpolarizing inhibitory postsynaptic potentials and hyperpolarizing response to gamma-aminobutyric acid in rabbit hippocampus studied in vitro. J. Neurosci. 4, 860-867. Murphy, T.H., Worley, P.F., and Baraban, J.M. (1991). L-type voltagesensitive calcium channels mediate synaptic activation of immediate early genes. Neuron 7, 625-635. Obrietan, K., and van den Pol, A.N. (1995). GABA neurotransmission in the hypothalamus: developmental reversal from Ca 2ϩ elevating to depressing. J. Neurosci. 15, 5065-5077. Obrietan, K., and van den Pol, A.N. (1997). GABA activity mediating cytosolic Ca 2ϩ rises in developing neurons is modulated by cAMPdependent signal transduction. J. Neurosci. 17, 4785-4799.
The Journal of Neuroscience, 2020
Synaptic plasticity is triggered by different patterns of network activity. Here, we investigated how LTP in CA3-CA1 synapses induced by different stimulation patterns is affected by tonic GABA A conductances in rat hippocampal slices. Spike-timingdependent LTP was induced by pairing Schaffer collateral stimulation with antidromic stimulation of CA1 pyramidal neurons. Theta-burst-induced LTP was induced by theta-burst stimulation of Schaffer collaterals. We mimicked increased tonic GABA A conductance by bath application of 30 lM GABA. Surprisingly, tonic GABA A conductance selectively suppressed theta-burstinduced LTP but not spike-timing-dependent LTP. We combined whole-cell patch-clamp electrophysiology, two-photon Ca 21 imaging, glutamate uncaging, and mathematical modeling to dissect the mechanisms underlying these differential effects of tonic GABA A conductance. We found that Ca 21 transients during pairing of an action potential with an EPSP were less sensitive to tonic GABA A conductance-induced shunting inhibition than Ca 21 transients induced by EPSP burst. Our results may explain how different forms of memory are affected by increasing tonic GABA A conductances under physiological or pathologic conditions, as well as under the influence of substances that target extrasynaptic GABA A receptors (e.g., neurosteroids, sedatives, antiepileptic drugs, and alcohol).
Scientific Reports, 2016
By acting on their ionotropic chloride channel receptors, GABA and glycine represent the major inhibitory transmitters of the central nervous system. Nevertheless, in various brain structures, depolarizing GABAergic/glycinergic postsynaptic potentials (dGPSPs) lead to dual inhibitory (shunting) and excitatory components, the functional consequences of which remain poorly acknowledged. Indeed, the extent to which each component prevails during dGPSP is unclear. Understanding the mechanisms predicting the dGPSP outcome on neural network activity is therefore a major issue in neurobiology. By combining electrophysiological recordings of spinal embryonic mouse motoneurons and modelling study, we demonstrate that increasing the chloride conductance (g Cl) favors inhibition either during a single dGPSP or during trains in which g Cl summates. Finally, based on this summation mechanism, the excitatory effect of EPSPs is overcome by dGPSPs in a frequency-dependent manner. These results reveal an important mechanism by which dGPSPs protect against the overexcitation of neural excitatory circuits. By acting on their ionotropic chloride channel receptor, GABA and glycine represent the major inhibitory amino acid transmitters of the central nervous system (CNS). These inhibitory transmitters control the input-output (I-O) relationship of excitatory drives impinging on neurons. However, under numerous circumstances, GABAergic/glycinergic postsynaptic potentials are depolarizing (dGPSPs) and exert mixed excitatory (depolarizing) and inhibitory (shunting) effects on the I-O relationship 1-7. From a functional perspective, dGPSPs control numerous crucial neuronal processes, such as spontaneous activities in the developing CNS 8,9 and tuning and gain-setting mechanisms 1,10. The effects of dGPSPs on the I-O relationship depend on the following major parameters: the driving force for chloride ions 11,12 , the peak chloride conductance g Clp , the neuronal input resistance (R in) and the spatial arrangement of these synapses 13. The inhibitory effect of dGPSPs on excitatory glutamatergic inputs largely depends on their relative timing 14 and location on the target neuron 1,13. The effect of dGPSPs is also controlled by other mechanisms, such as HCO3 − permeability of the GABA A /glycine receptors, changes in [K + ] o after massive synaptic activation of GABA A R 15 , and local differences in E Cl values in somatic, axonal and dendritic compartments 16. The relationship between the inhibitory and excitatory components of dGPSPs is therefore a complex phenomenon. Here, we address the relative roles of the excitatory (depolarization) and inhibitory (shunting) components of dGPSPs by a quantitative analysis of their interplay. We also consider the interaction of three parameters (E Cl , g Clp and E Rest) and their modulation by neuron passive properties. The present study addresses this question 1) by precisely assessing the magnitude and time course of the inhibitory and excitatory effects of a single dGPSP; 2) by analyzing the functional outcome of repetitive dGPSPs as a function of frequency; and 3) by considering their interaction with excitatory drives, which occurs in most neuronal types. For this purpose, a neuron that naturally exhibited various E Cl values and shapes (i.e., size and R in) was required. Therefore, we examined mouse spinal motoneurons (MNs), which express these parameter
Frontiers in Cellular Neuroscience
During development, hippocampal CA3 network generates recurrent population bursts, so-called Giant Depolarizing Potentials (GDPs). GDPs are characterized by synchronous depolarization and firing of CA3 pyramidal cells followed by afterhyperpolarization (GDP-AHP). Here, we explored the properties of GDP-AHP in CA3 pyramidal cells using gramicidin perforated patch clamp recordings from neonatal rat hippocampal slices. We found that GDP-AHP occurs independently of whether CA3 pyramidal cells fire action potentials (APs) or remain silent during GDPs. However, the amplitude of GDP-AHP increased with the number of APs the cells fired during GDPs. The reversal potential of the GDP-AHP was close to the potassium equilibrium potential. During voltageclamp recordings, current-voltage relationships of the postsynaptic currents activated during GDP-AHP were characterized by reversal near the potassium equilibrium potential and inward rectification, similar to the responses evoked by the GABA(B) receptor agonists. Finally, the GABA(B) receptor antagonist CGP55845 strongly reduced GDP-AHP and prolonged GDPs, eventually transforming them to the interictal and ictal-like discharges. Together, our findings suggest that the GDP-AHP involves two mechanisms: (i) postsynaptic GABA(B) receptor activated potassium currents, which are activated independently on whether the cell fires or not during GDPs; and (ii) activitydependent, likely calcium activated potassium currents, whose contribution to the GDP-AHP is dependent on the amount of firing during GDPs. We propose that these two complementary inhibitory postsynaptic mechanisms cooperate in the termination of GDP.