Mechanisms Involved in Tetanus-Induced Potentiation of Fast IPSCs in Rat Hippocampal CA1 Neurons

Abstract

In the present study, possible mechanisms involved in the tetanus-induced potentiation of gamma-aminobutyric acid-A (GABA-A) receptor-mediated inhibitory postsynaptic currents (IPSCs) were investigated using the whole cell voltage-clamp technique on CA1 neurons in rat hippocampal slices. Stimulations (100 Hz) of the stratum radiatum, while voltage-clamping the membrane potential of neurons, induces a long-term potentiation (LTP) of evoked fast IPSCs while increasing the number but not the amplitude of spontaneous IPSCs (sIPSCs). The potentiation of fast IPSCs was input specific. During the period of IPSC potentiation, postsynaptic responses produced by 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol hydrochloride and baclofen, GABA-A and GABA-B agonists respectively, were not significantly different from control. CGP 36742, a GABA-B antagonist, blocked the induction of tetanus-induced potentiation of evoked and spontaneous IPSCs, while GTPgammaS, an activator of G proteins, substitution for GTP in the postsynaptic recording electrode did not occlude potentiation. Since GABA-B receptors work through G proteins, our results suggest that pre- but not postsynaptic GABA-B receptors are involved in the potentiation of fast IPSCs. A tetanus delivered when GABA-A responses were completely blocked by bicuculline suggests that GABA-A receptor activation during tetanus is not essential for the induction of potentiation. Rp-cAMPs, an antagonist of protein kinase A (PKA) activation, blocks the induction of potentiation of fast IPSCs. Forskolin, an activator of PKA, increases baseline evoked IPSCs as well as the number of sIPSCs, and a tetanic stimulation during this enhancement uncovers a long-term depression of the evoked IPSC. Sulfhydryl alkylating agents, N-ethylmaleimide and p-chloromercuribenzoic acid, which have been found to presynaptically increase GABA release and have been suggested to have effects on proteins involved in transmitter release processes occurring in nerve terminals, occlude tetanus-induced potentiation of evoked and spontaneous IPSCs. Taken together our results suggest that LTP of IPSCs originates from a presynaptic site and that GABA-B receptor activation, cyclic AMP/PKA activation and sulfhydryl-alkylation are involved. Plasticity of IPSCs as observed in this study would have significant implications for network behavior in the hippocampus.

Differential Effects of Excitatory and Inhibitory Plasticity on Synaptically Driven Neuronal Input-Output Functions

“…Effective synaptic strength was manipulated using pharmacology, hyperpolarization, and directly through the induction of single-cell LTP. Given the difficulty in inducing plasticity exclusively at Inh→Ex synapses, uncertainties regarding the protocols that induce inhibitory plasticity, and the variability of results (Xie et al, 1995; Lu et al, 2000; Shew et al, 2000; Gaiarsa et al, 2002; Chevaleyre and Castillo, 2003), we limited our manipulations of inhibitory strength to pharmacological means to alter Inh→Ex transmission independently of the Ex→Ex and Ex→Inh strengths.…”

“…For example, from a computational perspective, what is the functional difference between potentiating excitatory inputs and depressing inhibitory ones? What is the computational benefit of potentiating both EPSPs and IPSPs onto the same postsynaptic neuron (Kairiss et al, 1987; Komatsu, 1994; Xie et al, 1995; Shew et al, 2000; Lamsa et al, 2005; Froemke et al, 2007), which superficially seems self-defeating?…”

Short Trains of Theta Frequency Stimulation Enhance CA1 Pyramidal Neuron Excitability in the Absence of Synaptic Potentiation

“…High-frequency stimulation protocols, in contrast, are unlikely to rely on disinhibition to induce plasticity. Importantly, previous studies have directly demonstrated plasticity of inhibitory synaptic transmission onto CA1 pyramidal cells (Shew et al, 2000; Lu et al, 2000; Chevaleyre and Castillo, 2003) or plasticity at excitatory synapses onto interneurons (Taube and Schwartzkroin, 1987; Ouardouz and Lacaille, 1995; McMahon and Kauer, 1997; Cowan et al, 1998). Thus it seems clear that I-LTD can make an important contribution to E-S potentiation induced by some forms of synaptic stimulation.…”

Ethanol Activation of Protein Kinase A Regulates GABAA Receptor Subunit Expression in the Cerebral Cortex and Contributes to Ethanol-Induced Hypnosis

“…Multiple electrophysiological studies have noted that PKA activity has differential effects on GABA A -R function. For instance, increasing PKA activity has increased GABA A -R responses in Purkinje neurons (Kano and Konnerth, 1992; Freund and Palmer, 1997), cerebellar interneurons (Nusser et al, 1999), hippocampal dentate granule cells (Kapur and Macdonald, 1996), CA1 neurons (Shew et al, 2000), hypoglossal motoneurons (Saywell and Feldman, 2004) as well as recombinant receptors (Angelotti et al, 1993). Conversely, PKA has been shown to reduce GABA A -R function in microsacs (Leidenheimer et al, 1991), cortical neurons (Tehrani et al, 1989), dorsal root ganglion neurons (White et al, 1992), recombinant receptors as well as primary neuronal cultures (Moss et al, 1992b), cerebellar granule cells (Robello et al, 1993), and hippocampal CA1 neurons (Poisbeau et al, 1999).…”