Effect of depolarizing GABA_A-mediated membrane responses on excitability of Cajal-Retzius cells in the immature rat neocortex

Abstract

However, it is difficult to draw conclusions about the functional consequences of subthreshold GABAergic depolarizations, since GABAergic membrane shunting and additional effects on voltage-dependent ion channels or action potential threshold must be considered. To systematically investigate factors that determine the GABAergic effect on neuronal excitability we performed whole cell patch-clamp recordings from Cajal-Retzius cells in immature rat neocortex, using [Cl Ϫ ] i between 10 and 50 mM. The effect of focal GABA application was quantified by measuring various parameters of GABAergic responses including the shift in minimal threshold current (rheobase). The rheobase shift was correlated with other parameters of the GABAergic responses by multiple linear regression analyses with a set of simple mathematical models. Our experiments demonstrate that focal GABA application induces heterogeneous rheobase shifts in Cajal-Retzius cells that could not be predicted reliably from [Cl Ϫ ] i or the GABAergic membrane depolarization. Implementation of a linear mathematical model, which takes the GABAergic membrane conductance and the difference between action potential threshold and GABA reversal potential into account, resulted in a close correlation between calculated and experimentally obtained rheobase shifts. Addition of a linear term proportional to the GABAergic membrane depolarization improved the accuracy of correlation. The main advantage of using multiple linear regression with simple models is that direction and strength of GABAergic excitability shifts can be analyzed by using only measured parameters of GABAergic responses and with minimal a priori information about cellular parameters. cortical development; shunting inhibition; intracellular chloride concentration; rheobase GABA IS THE MAIN INHIBITORY neurotransmitter in the adult nervous system and mediates its effect via ionotropic GABA A or GABA C receptors and metabotropic GABA B receptors (Emson

Local GABAergic signaling within sensory ganglia controls peripheral nociceptive transmission

“…Although neuronal membrane depolarization is usually associated with increased excitability, a large GABA A conductance can also produce a shunting effect preventing AP generation (39). We investigated the effects of GABA on AP firing in small-diameter (presumed nociceptive) cultured DRG neurons using the gramicidin-perforated patch clamp (gramicidin pores are impermeable to Cl – [ref.…”

GABA depolarizes immature neurons and inhibits network activity in the neonatal neocortex in vivo

“…Our data further revealed that the generation of Ca 2 þ clusters in the occipital cortex is essentially independent of NKCC1-in spite of its cellular effects (see above). Computational modelling and experimental studies in vitro have extensively characterized the conditions under which a subthreshold-depolarizing GABAergic conductance may facilitate action potential discharge (excitatory sensu lato) or, alternatively, inhibit neuronal output [20][21][22][23][24] . Although not excluding excitatory sensu lato actions of GABA, our data are compatible with the view that these, if present, are not required to drive spontaneous cortical network activity.…”

“…Owing to an increase in membrane conductance, depolarizing GABAergic inputs may modulate neuronal output in a complex and bidirectional manner. Whether excitatory or inhibitory effects on neuronal firing dominate eventually depends on multiple parameters (including membrane potential, reversal potential of GABA A Rmediated currents, action potential threshold 20 , timing and location of inputs [21][22][23] as well as previous neuronal activity 24,25 ).…”

Cajal–Retzius cells: Update on structural and functional properties of these mystic neurons that bridged the 20th century

“…5D; Mienville, 1998;Achilles et al, 2007). These depolarizing responses mediate an excitatory action in CRc (Mienville, 1998;Kolbaev et al, 2011a) and require an elevated intracellular Cl -concentration, which is maintained by the Na + , K + -2Cl À -symporter NKCC1 (Achilles et al, 2007). Due to the low transport capacity of NKCC1-mediated Cl À uptake GABAergic responses in CRc can be attenuated by sustained GABAergic activity (Kolbaev et al, 2011b).…”