Frequency‐dependent depression of inhibition in guinea‐pig neocortex in vitro by GABAB receptor feed‐back on GABA release.

Abstract

SUMMARY1. The mechanisms involved in the lability of inhibition at higher frequencies of stimulation were investigated in the guinea-pig in vitro neocortical slice preparation by intracellular recording techniques. We attempted to test the possibility of a feedback depression of GABA on subsequent release.2. At resting membrane potential (Em, -75-8 + 5-2 mV) stimulation of either the pial surface or subcortical white matter evoked a sequence of depolarizing and hyperpolarizing synaptic components in most neurones. An early hyperpolarizing component (IPSPA) was usually only obvious as a pronounced termination of the EPSP. followed by a later hyperpolarizing event (IPSPB). Current-voltage relationships revealed two different conductances of about 200 and 20 nS and reversal potentials of -73-0+444 and -88-6+6 1 mV for the early and late component. respectively.3. The conductances of IPSPA and IPSPB were fairly stable at a stimulus frequency of 0-1 Hz. At frequencies between 0-5 and 2 Hz both IPSPs were attenuated with the second stimulus and after about five stimuli a steady state was reached. Concomitantly IPSPs were shortened. The average decrease in synaptic conductance between 0-1 and 1 Hz was 80% for the IPSPA and 60% for the IPSPB. At these frequencies the reversal potentials decreased by 5 and 2 mV, respectively; Em and input resistance (Rin) were not consistently affected.4. The amplitudes of field potentials, action potentials and EPSPs of pyramidal cells were attenuated less than 10% at stimulus frequencies up to 1 Hz, suggesting that alterations in local circuits between the stimulation site and excitatory input onto inhibitory interneurones may play only a minor role in the frequency-dependent decav of IPSPs.5. Localized application of GABA produced multiphasic responses. With low concentrations and application near the soma an early hyperpolarization prevailed followed by a depolarizing late component. Brief application of GABA at low frequencies induced constant responses; at higher frequencies, the responses sometimes declined. were similar to each other and to the early IPSP. An apparently fivefold higher conductance was estimated at lower Ems, suggesting that the GABA response had a voltage sensitivity. The slope conductance of IPSPs was decreased by up to 50 % for tens of seconds after postsynaptically detectable effects of GABA had dissipated. 6. Application of the GABA uptake inhibitor nipecotic acid (50-500 JLM) reduced the conductance of both components of orthodromically evoked inhibition and shortened the IPSP at low frequencies, but had no additional effects at higher stimulation rates. Em and Rin were not consistently affected. Application of nipecotic acid usually decreased the latency and increased the slope conductance of GABA responses. Depression of IPSPs by nipecotic acid at low frequencies, in the face of enhanced GABA responses, is probably presynaptically mediated. The prolonged time course of synaptically liberated GABA by nipecotic acid may cause extended presynaptic effects.7. ...

Input-specific effects of acetylcholine on sensory and intracortical evoked responses in the “barrel cortex” in vivo

“…In sUce preparations, GABA and other neurotransmitters have been shown to act presynaptically to produce frequency-dependent depression of IPSPs (Deisz & Prince, 1989) and EPSPs (Kang, 1995). Thus, depression observed at longer inter-stimulus intervals may be due to substances acting presynaptically to modulate the probability of release (Castro-Alamancos, 1997).…”

Properties of GABAAReceptors Underlying Inhibitory Synaptic Currents in Neocortical Pyramidal Neurons

“…Thus the depression in the amplitude of the IPSCs observed with paired stimulation of neocortical GABAergic synapses (Deisz and Prince, 1989;Fleidervish and Gutnick, 1995;Thomson et al, 1996) could be explained, at least partially, by accumulation of receptors in desensitized states. It is important to note, however, that the effect of receptor desensitization during repetitive stimulation would be minimized if the GABA A receptors are not saturated during synaptic transmission.…”

Comparison of antagonist potencies at pre‐ and post‐synaptic GABAB receptors at inhibitory synapses in the CA1 region of the rat hippocampus

“…In this respect, in the CA1 region of the hippocampus, physiological activation of postsynaptic GABA B receptors results in the late inhibitory postsynaptic potential (IPSP B ) (Dutar & Nicoll, 1998a;Soltesz et al, 1988;Otis et al, 1993;SolõÂ s & Nicoll, 1992) whereas activation of presynaptic GABA B receptors results in pairedpulse depression of synaptic inhibition (i.e. a GABA B autoreceptor e ect: Thompson & GaÈ hwiler, 1989;Deisz & Prince, 1989;Davies et al, 1990;Olpe et al, 1994) which causes paired-pulse widening of synaptic excitation (Nathan et al, 1990;Nathan & Lambert, 1991;Davies & Collingridge, 1996). By determining the IC 50 values for antagonism of the late IPSP, and comparing these with those for antagonism of paired-pulse widening of EPSPs for six structurally di erent GABA B receptor antagonists, we have attempted to address whether synaptically activated pre-and post-synaptic GABA B receptors at GABAergic synapses can be di erentiated pharmacologically.…”