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Short-term ionic plasticity at GABAergic synapses.

Raimondo JV, Markram H, Akerman CJ - Front Synaptic Neurosci (2012)

Bottom Line: This involves short-lasting changes to the ionic driving force for the post-synaptic receptors, a process referred to as short-term ionic plasticity.These changes are directly related to the history of activity at inhibitory synapses and are influenced by a variety of factors including the location of the synapse and the post-synaptic cell's ion regulation mechanisms.We explore the processes underlying this form of plasticity, when and where it can occur, and how it is likely to impact network activity.

View Article: PubMed Central - PubMed

Affiliation: Akerman Lab, Department of Pharmacology, Oxford University Oxford, Oxfordshire, UK.

ABSTRACT
Fast synaptic inhibition in the brain is mediated by the pre-synaptic release of the neurotransmitter γ-Aminobutyric acid (GABA)and the post-synaptic activation of GABA-sensitive ionotropic receptors. As with excitatory synapses, it is being increasinly appreciated that a variety of plastic processes occur at inhibitory synapses, which operate over a range of timescales. Here we examine a form of activity-dependent plasticity that is somewhat unique to GABAergic transmission. This involves short-lasting changes to the ionic driving force for the post-synaptic receptors, a process referred to as short-term ionic plasticity. These changes are directly related to the history of activity at inhibitory synapses and are influenced by a variety of factors including the location of the synapse and the post-synaptic cell's ion regulation mechanisms. We explore the processes underlying this form of plasticity, when and where it can occur, and how it is likely to impact network activity.

No MeSH data available.


Related in: MedlinePlus

Biphasic responses to intense GABAAR activation are caused by a rapid shift from hyperpolarizing to depolarizing EGABA. (Left) a schematic of a patched pyramidal neuron receiving strong GABAAR input either via stimulation of GABAergic afferents or application of GABA. (Right) traces showing the putative changes in ionic and synaptic parameters as a result of the GABAAR activation. Separate traces show the cell's membrane potential (Vm, black); the GABAAR conductance (gGABA, red), the reversal potentials for the GABAAR (EGABA, gray dashed), HCO−3 (EHCO3, green) and chloride (ECl−, blue); plus the extracellular K+ concentration ([K+]out, black). Insets (within dashed boxes) show transmembrane ion fluxes and gradients at two points during the response to GABAAR activation. At the start of GABAAR activation (left inset) [Cl−] is typically much higher outside neurons (e.g., 135 mM) as opposed to inside neurons (e.g., 6 mM). In contrast, [HCO−3] is only moderately higher outside (23 mM) as compared to inside (12 mM). Therefore at a typical resting membrane potential of −60 mV, when GABA (red wedge) binds to ionotropic GABAARs, Cl− flows into the cell (blue arrow) while HCO−3 flows out (green arrow). As GABAARs are approximately four times more permeable to Cl− than to HCO−3 ions (Kaila and Voipio, 1987), the bulk of anion flux through the receptors is Cl−. This causes the membrane potential hyperpolarization typical of classic GABAAR mediated inhibition. With continued GABAAR activation (right inset), Cl− influx ultimately exceeds Cl− extrusion mechanisms and a reduction in the transmembrane Cl− gradient occurs (Staley and Proctor, 1999). A corresponding depletion of intracellular HCO−3 is prevented by the activity of carbonic anhydrase, which uses CO2 as a substrate to rapidly regenerate HCO−3 (Rivera et al., 2005). As a result, ECl− (blue trace) and hence EGABA shift toward the more positive EHCO−3 (green trace) causing the membrane depolarization typical of the biphasic GABAergic response. Intracellular Cl− accumulation also results in the delayed extrusion of K+ into the extracellular space via the Cl−/K+ cotransporter KCC2. This further contributes to the late-stage depolarization of the biphasic response (Kaila et al., 1997; Viitanen et al., 2010).
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Figure 1: Biphasic responses to intense GABAAR activation are caused by a rapid shift from hyperpolarizing to depolarizing EGABA. (Left) a schematic of a patched pyramidal neuron receiving strong GABAAR input either via stimulation of GABAergic afferents or application of GABA. (Right) traces showing the putative changes in ionic and synaptic parameters as a result of the GABAAR activation. Separate traces show the cell's membrane potential (Vm, black); the GABAAR conductance (gGABA, red), the reversal potentials for the GABAAR (EGABA, gray dashed), HCO−3 (EHCO3, green) and chloride (ECl−, blue); plus the extracellular K+ concentration ([K+]out, black). Insets (within dashed boxes) show transmembrane ion fluxes and gradients at two points during the response to GABAAR activation. At the start of GABAAR activation (left inset) [Cl−] is typically much higher outside neurons (e.g., 135 mM) as opposed to inside neurons (e.g., 6 mM). In contrast, [HCO−3] is only moderately higher outside (23 mM) as compared to inside (12 mM). Therefore at a typical resting membrane potential of −60 mV, when GABA (red wedge) binds to ionotropic GABAARs, Cl− flows into the cell (blue arrow) while HCO−3 flows out (green arrow). As GABAARs are approximately four times more permeable to Cl− than to HCO−3 ions (Kaila and Voipio, 1987), the bulk of anion flux through the receptors is Cl−. This causes the membrane potential hyperpolarization typical of classic GABAAR mediated inhibition. With continued GABAAR activation (right inset), Cl− influx ultimately exceeds Cl− extrusion mechanisms and a reduction in the transmembrane Cl− gradient occurs (Staley and Proctor, 1999). A corresponding depletion of intracellular HCO−3 is prevented by the activity of carbonic anhydrase, which uses CO2 as a substrate to rapidly regenerate HCO−3 (Rivera et al., 2005). As a result, ECl− (blue trace) and hence EGABA shift toward the more positive EHCO−3 (green trace) causing the membrane depolarization typical of the biphasic GABAergic response. Intracellular Cl− accumulation also results in the delayed extrusion of K+ into the extracellular space via the Cl−/K+ cotransporter KCC2. This further contributes to the late-stage depolarization of the biphasic response (Kaila et al., 1997; Viitanen et al., 2010).

Mentions: The situation within the GABAergic system is quite different. As described above, the major ionotropic receptor for GABA, the GABAAR, is permeable primarily to Cl− and to a lesser extent HCO−3 (Kaila and Voipio, 1987; Kaila et al., 1989). Therefore at rest, EGABA (typically −75 mV) is considerably closer to the very negative Cl− reversal (ECl−; typically −85 mV) than the more positive HCO−3 reversal (EHCO−3; typically −20 mV) (Kaila et al., 1993; Lambert and Grover, 1995). During intense activation of GABAARs however, rapid Cl− influx can exceed Cl− extrusion mechanisms and a reduction in the transmembrane Cl− gradient occurs (Kaila and Voipio, 1987; Kaila et al., 1989; Staley et al., 1995; Staley and Proctor, 1999). It is thought that a corresponding collapse of the HCO−3 gradient is prevented by the activity of intra- and extra-cellular carbonic anhydrases, which use CO2 as a substrate to rapidly regenerate intracellular HCO−3 (Kaila et al., 1990; Rivera et al., 2005). As a result, the intracellular Cl− accumulation that occurs during repeated activation of GABAARs means that ECl− and hence EGABA shift toward the more positive EHCO−3 (Figure 1). Such a process is thought to contribute to short-term synaptic depression of GABAergic potentials (McCarren and Alger, 1985; Huguenard and Alger, 1986).


Short-term ionic plasticity at GABAergic synapses.

Raimondo JV, Markram H, Akerman CJ - Front Synaptic Neurosci (2012)

Biphasic responses to intense GABAAR activation are caused by a rapid shift from hyperpolarizing to depolarizing EGABA. (Left) a schematic of a patched pyramidal neuron receiving strong GABAAR input either via stimulation of GABAergic afferents or application of GABA. (Right) traces showing the putative changes in ionic and synaptic parameters as a result of the GABAAR activation. Separate traces show the cell's membrane potential (Vm, black); the GABAAR conductance (gGABA, red), the reversal potentials for the GABAAR (EGABA, gray dashed), HCO−3 (EHCO3, green) and chloride (ECl−, blue); plus the extracellular K+ concentration ([K+]out, black). Insets (within dashed boxes) show transmembrane ion fluxes and gradients at two points during the response to GABAAR activation. At the start of GABAAR activation (left inset) [Cl−] is typically much higher outside neurons (e.g., 135 mM) as opposed to inside neurons (e.g., 6 mM). In contrast, [HCO−3] is only moderately higher outside (23 mM) as compared to inside (12 mM). Therefore at a typical resting membrane potential of −60 mV, when GABA (red wedge) binds to ionotropic GABAARs, Cl− flows into the cell (blue arrow) while HCO−3 flows out (green arrow). As GABAARs are approximately four times more permeable to Cl− than to HCO−3 ions (Kaila and Voipio, 1987), the bulk of anion flux through the receptors is Cl−. This causes the membrane potential hyperpolarization typical of classic GABAAR mediated inhibition. With continued GABAAR activation (right inset), Cl− influx ultimately exceeds Cl− extrusion mechanisms and a reduction in the transmembrane Cl− gradient occurs (Staley and Proctor, 1999). A corresponding depletion of intracellular HCO−3 is prevented by the activity of carbonic anhydrase, which uses CO2 as a substrate to rapidly regenerate HCO−3 (Rivera et al., 2005). As a result, ECl− (blue trace) and hence EGABA shift toward the more positive EHCO−3 (green trace) causing the membrane depolarization typical of the biphasic GABAergic response. Intracellular Cl− accumulation also results in the delayed extrusion of K+ into the extracellular space via the Cl−/K+ cotransporter KCC2. This further contributes to the late-stage depolarization of the biphasic response (Kaila et al., 1997; Viitanen et al., 2010).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 1: Biphasic responses to intense GABAAR activation are caused by a rapid shift from hyperpolarizing to depolarizing EGABA. (Left) a schematic of a patched pyramidal neuron receiving strong GABAAR input either via stimulation of GABAergic afferents or application of GABA. (Right) traces showing the putative changes in ionic and synaptic parameters as a result of the GABAAR activation. Separate traces show the cell's membrane potential (Vm, black); the GABAAR conductance (gGABA, red), the reversal potentials for the GABAAR (EGABA, gray dashed), HCO−3 (EHCO3, green) and chloride (ECl−, blue); plus the extracellular K+ concentration ([K+]out, black). Insets (within dashed boxes) show transmembrane ion fluxes and gradients at two points during the response to GABAAR activation. At the start of GABAAR activation (left inset) [Cl−] is typically much higher outside neurons (e.g., 135 mM) as opposed to inside neurons (e.g., 6 mM). In contrast, [HCO−3] is only moderately higher outside (23 mM) as compared to inside (12 mM). Therefore at a typical resting membrane potential of −60 mV, when GABA (red wedge) binds to ionotropic GABAARs, Cl− flows into the cell (blue arrow) while HCO−3 flows out (green arrow). As GABAARs are approximately four times more permeable to Cl− than to HCO−3 ions (Kaila and Voipio, 1987), the bulk of anion flux through the receptors is Cl−. This causes the membrane potential hyperpolarization typical of classic GABAAR mediated inhibition. With continued GABAAR activation (right inset), Cl− influx ultimately exceeds Cl− extrusion mechanisms and a reduction in the transmembrane Cl− gradient occurs (Staley and Proctor, 1999). A corresponding depletion of intracellular HCO−3 is prevented by the activity of carbonic anhydrase, which uses CO2 as a substrate to rapidly regenerate HCO−3 (Rivera et al., 2005). As a result, ECl− (blue trace) and hence EGABA shift toward the more positive EHCO−3 (green trace) causing the membrane depolarization typical of the biphasic GABAergic response. Intracellular Cl− accumulation also results in the delayed extrusion of K+ into the extracellular space via the Cl−/K+ cotransporter KCC2. This further contributes to the late-stage depolarization of the biphasic response (Kaila et al., 1997; Viitanen et al., 2010).
Mentions: The situation within the GABAergic system is quite different. As described above, the major ionotropic receptor for GABA, the GABAAR, is permeable primarily to Cl− and to a lesser extent HCO−3 (Kaila and Voipio, 1987; Kaila et al., 1989). Therefore at rest, EGABA (typically −75 mV) is considerably closer to the very negative Cl− reversal (ECl−; typically −85 mV) than the more positive HCO−3 reversal (EHCO−3; typically −20 mV) (Kaila et al., 1993; Lambert and Grover, 1995). During intense activation of GABAARs however, rapid Cl− influx can exceed Cl− extrusion mechanisms and a reduction in the transmembrane Cl− gradient occurs (Kaila and Voipio, 1987; Kaila et al., 1989; Staley et al., 1995; Staley and Proctor, 1999). It is thought that a corresponding collapse of the HCO−3 gradient is prevented by the activity of intra- and extra-cellular carbonic anhydrases, which use CO2 as a substrate to rapidly regenerate intracellular HCO−3 (Kaila et al., 1990; Rivera et al., 2005). As a result, the intracellular Cl− accumulation that occurs during repeated activation of GABAARs means that ECl− and hence EGABA shift toward the more positive EHCO−3 (Figure 1). Such a process is thought to contribute to short-term synaptic depression of GABAergic potentials (McCarren and Alger, 1985; Huguenard and Alger, 1986).

Bottom Line: This involves short-lasting changes to the ionic driving force for the post-synaptic receptors, a process referred to as short-term ionic plasticity.These changes are directly related to the history of activity at inhibitory synapses and are influenced by a variety of factors including the location of the synapse and the post-synaptic cell's ion regulation mechanisms.We explore the processes underlying this form of plasticity, when and where it can occur, and how it is likely to impact network activity.

View Article: PubMed Central - PubMed

Affiliation: Akerman Lab, Department of Pharmacology, Oxford University Oxford, Oxfordshire, UK.

ABSTRACT
Fast synaptic inhibition in the brain is mediated by the pre-synaptic release of the neurotransmitter γ-Aminobutyric acid (GABA)and the post-synaptic activation of GABA-sensitive ionotropic receptors. As with excitatory synapses, it is being increasinly appreciated that a variety of plastic processes occur at inhibitory synapses, which operate over a range of timescales. Here we examine a form of activity-dependent plasticity that is somewhat unique to GABAergic transmission. This involves short-lasting changes to the ionic driving force for the post-synaptic receptors, a process referred to as short-term ionic plasticity. These changes are directly related to the history of activity at inhibitory synapses and are influenced by a variety of factors including the location of the synapse and the post-synaptic cell's ion regulation mechanisms. We explore the processes underlying this form of plasticity, when and where it can occur, and how it is likely to impact network activity.

No MeSH data available.


Related in: MedlinePlus