Use-dependent depression of IPSPs in rat hippocampal pyramidal cells in vitro

Abstract

We have used intracellular recording techniques to study the use-dependence of evoked inhibitory postsynaptic potentials (IPSPs) in rat CA1 hippocampal pyramidal cells. We determined reversal potentials and conductance changes associated with IPSPs and responses to directly applied gamma-aminobutyric acid (GABA). The IPSP depression could be seen after a single conditioning stimulus. This depression appeared to be due primarily to a 50% decrease in IPSP conductance (gIPSP). Trains of stimulating pulses (50 pulses at 5 or 10 Hz) produced more pronounced effects than a single conditioning pulse. Suprathreshold repetitive stimulation of stratum radiatum (SR) produced epileptiform burst firing and greater depression of IPSPs than did alvear (ALV) or subthreshold SR stimulation. During suprathreshold SR stimulation the IPSP was nearly abolished and the membrane potential could become less negative than the resting potential. A masking effect of facilitated depolarizing potentials on IPSPs was unlikely since IPSPs accompanied by little or no depolarizing potential were also depressed by SR trains. The 75% reduction in IPSP conductance found after repetitive stimulation confirmed that an overlapping conductance was not responsible for the depression of the IPSP. The GABA-induced conductance increase was not depressed by identical trains. Trains of stimulation induced depolarizing shifts in equilibrium potentials for the IPSP (EIPSP) and GABA (EGABA) of approximately 10 mV. These shifts were always greater after SR trains than after ALV trains. Simultaneous recordings of membrane potential and extracellular potassium concentration ([K+]o) with K+-sensitive microelectrodes revealed a direct correlation between the two during a stimulus train. Membrane potential depolarized as much as 18 mV from the peak of the IPSP and [K+]o could increase to a maximum of 10 mM during some trains. A depressant effect (of approximately 50%) of K+ on IPSPs was demonstrated by brief pressure ejection of K+ near the soma. We conclude that repetitive stimulation depresses gIPSP and shifts EIPSP in the depolarizing direction. Whereas gIPSP began to decline after a single conditioning pulse, the additional depression of IPSPs produced by stimulus trains was due in large part to shifts in EIPSP. Depression of gIPSP was not due to desensitization or block of ionic conductances, since gGABA was not reduced. The EIPSP may change as a result of increases in [K+]o.

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

“…The marked depression of both inhibitory components at comparatively low rates of stimulation corroborates and extends previous investigations on frequencydependent, depression of IPSI's (Curtis & Eccles, 1960;Ben-Ari et al 1979;McCarren & Alger, 1985). This attenuation occurs in a frequency range where no significant effects on EPSPs are detectable.…”

“…The decline of IPSPs at higher frequencies of FREQU TENCY DEPENYDENCE OF NEOCORTICA L IVHIBITION 515 stimulation in hippocampal neurones in vitro is associated with changes in conductance and the ionic gradient (McCarrent & Alger, 1985) anid fadinlg of GABA responses has been attributed to shifts of the Cl-equilibrium potential (Segal & Barker, 1984;Huguenard & Alger., 1986). The concomitant extracellular K' changes reported (McCarren & Alger, 1985) may have also affected the inhibitory gradient.…”

“…1988a). The rather low experimental temperature used in earlier experiments (McCarren & Alger, 1985) might have impaired temperature-sensitive transport mnechanisms such as Cl-extrusion (Thompson et al , 1988b) and the Na'-K' pump Contribution of postsynaptic sensitivity changes to IPSP decline A crucial experiment for excluding postsynaptic sensitivity changes as a cause for the decline in IPSP conductance would be its comparison with GABA-induced conductance before and after a series of IPSPs. Such a comparison is not possible within the required accuracy, since GABA application reduced IPSP.…”

“…Inhibitory postsynaptic potentials (IPSPs) were also shown to be reduced at higher frequencies of stimulation in motoneurones (Curtis & Eccles, 1960), hippocampal pyramidal cells in vivo (Ben-Ari, Krnjevic & Reinhardt, 1979) and in vitro (McCarren & Alger, 1985) and in neocortical cells (Connors, Gutnick & Prince, 1982). Like drug-induced depression of lPSPs, frequency-dependent attenuation may facilitate the onset of abnormal neuronal discharges.…”

GABAA receptor function is regulated by phosphorylation in acutely dissociated guinea‐pig hippocampal neurones.

“…Although the exact function of GABAergic inhibition in the integrative activity of the cortex remains unclear, its importance is underscored by studies showing that the pharmacological blockade of GABAA receptor lead to epileptiform activity (Schwartzkroin & Prince, 1980) and that deficiencies in the GABAergic inhibitory system may be involved in some forms of human epilepsy (Lloyds, Bossi, Morselli, Munari, Rougier & Loiseau, 1986). In addition, modification of inhibition may be involved in both short-term (Ben-Ari, Krnjevic & Reinhardt, 1979;XXTong & Wlatkins, 1982;McCarren &, Alger, 1985;Thompson & Gaehwiler, 1989) and long-term (Stelzer, Slater & ten Bruggencate, 1987; Miles & Wong, 1987) changes in neuronal activity following tetanic stimulation of afferent fibres to the hippocampus. Simulation studies (Traub, Miles & Wong, 1989), based on data obtained from the hippocampal slice preparation, showed that reverberating, synchronized activity appears in groups of hippocampal cells when inhibition is reduced.…”