Dual personality of GABA/glycine-mediated depolarizations in immature spinal cord

Abstract

The inhibitory action of glycine and GABA in adult neurons consists of both shunting incoming excitations and moving the membrane potential away from the action potential (AP) threshold. By contrast, in immature neurons, inhibitory postsynaptic potentials (IPSPs) are depolarizing; it is generally accepted that, despite their depolarizing action, these IPSPs are inhibitory because of the shunting action of the Cl ؊ conductance increase. Here we investigated the integration of depolarizing IPSPs (dIPSPs) with excitatory inputs in the neonatal rodent spinal cord by means of both intracellular recordings from lumbar motoneurons and a simulation using the compartment model program ''Neuron.'' We show that the ability of IPSPs to suppress suprathreshold excitatory events depends on E Cl and the location of inhibitory synapses. The depolarization outlasts the conductance changes and spreads electrotonically in the somatodendritic tree, whereas the shunting effect is restricted and local. As a consequence, dIPSPs facilitated AP generation by subthreshold excitatory events in the late phase of the response. The window of facilitation became wider as E Cl was more depolarized and started earlier as inhibitory synapses were moved away from the excitatory input. GAD65/67 immunohistochemistry demonstrated the existence of distal inhibitory synapses on motoneurons in the neonatal rodent spinal cord. This study demonstrates that small dIPSPs can either inhibit or facilitate excitatory inputs depending on timing and location. Our results raise the possibility that inhibitory synapses exert a facilitatory action on distant excitatory inputs and slight changes of E Cl may have important consequences for network processing.chloride homeostasis ͉ facilitation ͉ inhibition ͉ synaptic integration G ABA and glycine are excitatory in the immature spinal cord and become inhibitory during development. The shift from depolarizing to hyperpolarizing inhibitory postsynaptic potentials (IPSPs) occurs during the first postnatal week (1), a time window during which motoneurons (MNs) undergo considerable maturation of membrane properties (see ref. 2 for review). Some 15 years after the demonstration that GABA and glycine depolarize immature neurons (3-12), the excitatory or inhibitory nature of these depolarizations is still a matter of debate. A critical factor appears to be the equilibrium potential for Cl Ϫ ions (E Cl ) relative to action potential (AP) threshold. Spinal cord neurons in 4-to 7-day-old cultures exhibit spontaneous firing that is depressed by application of bicuculline to block GABA A receptors, suggesting that GABA release from developing axons can drive sodium APs (13). Similarly, a brief application of glycine onto the in vitro spinal cord isolated from fetal rats, at embryonic day 15.5 (i.e., 1 week before birth), evokes excitatory responses that are abolished by strychnine (14). Therefore, there is no doubt that GABA and glycine can play an excitatory role at an early stage of the development of spinal MNs and interneuron...

Compensatory Enhancement of Intrinsic Spiking upon NKCC1 Disruption in Neonatal Hippocampus

“…3A). Prolonged application led to complete suppression of fGDPs in both genotypes, which is expected because of the collapse of the Cl Ϫ gradient (WT) and of the shunting inhibitory action of GABA (Khalilov et al, 1999;Jean-Xavier et al, 2007). That a tonic depolarization promotes fGDPs in both WT and NKCC1 Ϫ/Ϫ slices was verified in experiments in which an elevation of extracellular K ϩ increased their frequency (data not shown; n ϭ 6 and n ϭ 4, respectively) (cf.…”

Activation of 5-HT2A receptors upregulates the function of the neuronal K-Cl cotransporter KCC2

“…The expression or the function of KCC2 is reduced in several neurological disorders (2,4), and the resulting slight increase in [Cl -] i (depolarizing shift of the chloride equilibrium potential, E Cl ) dramatically compromises the inhibitory control of firing rate and excitatory inputs (5)(6)(7). Given the role of KCC2 in regulating the strength of inhibitory synaptic transmission, identifying tools that may increase KCC2 function and, hence, restore endogenous inhibition in pathological conditions is of particular importance.…”

Une nouvelle cible thérapeutique dans le traitement de la spasticité après une lésion de la moelle épinière : la calpaïne

“…Les principaux neurotransmetteurs de la moelle épinière que sont le GABA et la glycine agissent sur des récepteurs membranaires perméables aux ions chlore (Cl Dans des conditions normales, la concentration intracellulaire de ces ions est maintenue basse grâce à la présence du co-transporteur KCC2 (K-Cl co-transporter 2) à la membrane des neurones qui expulse l'ion de la cellule (Figure 2c) [17]. En raison de leur faible concentration intracellulaire, les ions Cl -entrent dans le neurone lors de l'ouverture des récepteurs GABA A 4 et glycine 5 , et génèrent une hyperpolarisation du potentiel de membrane et donc une inhibition du neurone (Figure 2c).…”