Development of a tonic form of synaptic inhibition in rat cerebellar granule cells resulting from persistent activation of GABAA receptors.

Abstract

I To investigate the origin and functional significance of a recently described tonic GABAA receptor-mediated conductance in cerebellar granule cells we have made recordings from cells in cerebellar slices from rats of different ages (postnatal days P4 to P28). 2. During development there was a dramatic change in the properties of GABA-mediated synaptic transmission. The contribution to GABAA receptor-mediated charge transfer from the tonic conductance (GGABA), relative to that resulting from discrete spontaneous postsynaptic currents (sPSCs), was increased from 5 % at P7 to 99 % at P21. GGABA was reduced by bicuculline, tetrodotoxin and by lowering extracellular Ca2+, and was initially present only in those cells which exhibited sPSCs. 3. At P7 sPSCs were depolarizing, occasionally triggering a single action potential. By P18 the GABA reversal potential was shifted close to the resting potential and GGABA produced a shunting inhibition. Removal of GGABA by bicuculline increased granule cell excitability in response to current injection. 4. This novel tonic inhibition is present despite the low number of Golgi cell synapses on individual granule cells and appears to result from 'overspill' of synaptically released GABA leading to activation of synaptic and extrasynaptic GABAA receptors.

Synaptically Evoked GABA Transporter Currents in Neocortical Glia

“…However, the activation of GABA A receptors less susceptible to desensitization (e.g., Macdonald 1994, 1996) may occur via spillover. The observation that extrasynaptic GABA concentrations are capable of reaching micromolar concentration levels several milliseconds following release support the notion of crosstalk between neighboring synapses as has been reported elsewhere (Barbour and Häusser 1997;Brickley et al 1996;Isaacson et al 1993;Kullmann et al 1996;Rossi and Hamann 1998). Our estimate of 6 M is based on the integral of the stimulus-evoked transporter current.…”

GABA Regulates Dendritic Growth by Stabilizing Lamellipodia in Newly Generated Interneurons of the Olfactory Bulb

“…This hypothesis received strong support from our observations with calcium imaging demonstrating that GABA A receptors present on these cells are able to respond tonically to GABA. Hence, similar to neurons in the hippocampus and the cerebellum (Brickley et al, 1996;Hamann et al, 2002;Nusser and Mody, 2002), subventricular zone-derived neurons may express GABA A receptors that are persistently open and slowly desensitizing. The idea of tonic activation of GABA A receptors through autocrine/paracrine signaling loop in SVZ cells is in line with previous reports showing that newly generated neurons are able to produce and spontaneously liberate GABA (Bolteus and Bordey, 2004;Bolteus et al, 2005).…”

Propofol enhances both tonic and phasic inhibitory currents in second-order neurons of the solitary tract nucleus (NTS)

“…The use of adult rats avoided the developmentally transient expression of potential target proteins including GABA mechanisms observed in the brainstem (Awatramani et al, 2004) as well as cortical neurons (Brickley et al, 1996). The high level of experimental precision offered by ST-evoked EPSC measures in second order NTS neurons makes the negative result of propofol effects on ST responses particularly remarkable since multiple presynaptic properties are assessed that include conduction sites along the afferent axon as well as the terminal release site itself (Bailey et al, 2006b).…”

“…Total propofol concentrations of 10 -30 µM were required in NTS neurons to induce a persistent, inhibitory tonic current. Tonic GABA A currents increase during development in cerebellar neurons (Brickley et al, 1996) and anesthetic sensitivity of tonic currents can be much greater than for phasic events, for example Belelli et al (2005). The relative insensitivity of tonic currents in NTS neurons for propofol contrasts with the high sensitivity for tonic GABA A currents in hippocampal and neocortical neurons to propofol and isoflurane (Bai et al, 2001;Caraiscos et al, 2004a;Caraiscos et al, 2004b;Drasbek et al, 2007).…”