Simultaneous NMDA-Dependent Long-Term Potentiation of EPSCs and Long-Term Depression of IPSCs in Cultured Rat Hippocampal Neurons

Abstract

A fundamental issue in understanding activity-dependent long-term plasticity of neuronal networks is the interplay between excitatory and inhibitory synaptic drives in the network. Using dual whole-cell recordings in cultured hippocampal neurons, we examined synaptic changes occurring as a result of a transient activation of NMDA receptors in the network. This enhanced transient activation led to a long-lasting increase in synchrony of spontaneous activity of neurons in the network. Simultaneous long-term potentiation of excitatory synaptic strength and a pronounced long-term depression of inhibitory synaptic currents (LTDi) were produced, which were independent of changes in postsynaptic potential and Ca 2ϩ concentrations. Surprisingly, miniature inhibitory synaptic currents were not changed by the conditioning, whereas both frequency and amplitudes of miniature EPSCs were enhanced. LTDi was mediated by activation of a presynaptic GABA B receptor, because it was blocked by saclofen and CGP55845 [(2S)-3-{[(15)-1-(3,4-dichlorophenyl)ethyl]amino-2-hydroxypropyl)(phenylmethyl)phosphinic acid].The cAMP antagonist Rp-adenosine 3Ј,5Ј-cyclic monophosphothioate abolished all measured effects of NMDA-dependent conditioning, whereas a nitric oxide synthase inhibitor was ineffective. Finally, network-induced plasticity was not occluded by a previous spike-timing-induced plasticity, indicating that the two types of plasticity may not share the same mechanism. These results demonstrate that network plasticity involves opposite affects on inhibitory and excitatory neurotransmission.

NMDA Receptor Activation Potentiates Inhibitory Transmission through GABA Receptor-Associated Protein-Dependent Exocytosis of GABAAReceptors

“…Previous reports have identified that LTP-inducing stimuli at glutamatergic synapses in the hippocampus can simultaneously potentiate excitatory and depress inhibitory transmission (Chevaleyre and Castillo, 2003;Ivenshitz and Segal, 2006). To our knowledge, however, there is no evidence of glutamatergic stimuli that concurrently depress excitatory transmission and enhance inhibition.…”

Synaptopodin Regulates Plasticity of Dendritic Spines in Hippocampal Neurons

“…Although it is not associated with a specific class of spines (stubby, mushroom, long), SP is more prevalent in spines with a large head that are innervated by synaptophysin-containing terminals. The presence of SP in spines correlates with the presence and efficacy of functional GluRs of the AMPA type, but not of the NMDA type and its presence is upregulated by a transient activation of the NMDA-R that causes a long lasting potentiation of synaptic connectivity (Ivenshitz and Segal, 2006). SP has been associated with the spine apparatus, a membranous extension of the dendritic smooth endoplasmic reticulum.…”

“…A transient (5 min) intense activation of synaptic NMDA-R has been reported to produce a long-lasting increase in excitatory postsynaptic current magnitudes recorded between pairs of neurons in culture (Ivenshitz and Segal, 2006) and to enhance the delivery of GluR1-clusters into dendritic spine heads (Korkotian and Segal, 2007). We examined the effect of chemical LTP (cLTP) on SP puncta in dendritic spine heads using immunostaining for endogenous SP in GFP-transfected cells (Fig.…”

Mechanisms underlying rule learning-induced enhancement of excitatory and inhibitory synaptic transmission

“…It has been previously shown that GABA Breceptors mediate inhibition of synaptic release through modulation of presynaptic Ca 2ϩ channels Carter 2010, 2011;Marshall 2008;Otmakhova and Lisman 2004;Tang and Hasslemo 1994). In particular, activity-induced GABA B -dependent plasticity was attributed to activation of presynaptic receptors of inhibitory neurons (Ivenshitz and Segal 2006). According to this scenario, the first stimulus in a paired-pulse protocol causes a GABA transient that reduces release during the second pulse, through a di-synaptic mechanism.…”