Anti-Hebbian Long-Term Potentiation in the Hippocampal Feedback Inhibitory Circuit

Abstract

Long-term potentiation (LTP), which approximates Hebb's postulate of associative learning, typically requires depolarization-dependent glutamate receptors of the NMDA (N-methyl-Daspartate) subtype. However, in some neurons, LTP depends instead on calcium-permeable AMPA-type receptors. This is paradoxical because intracellular polyamines block such receptors during depolarization. We report that LTP at synapses on hippocampal interneurons mediating feedback inhibition is "anti-Hebbian": It is induced by presynaptic activity but prevented by postsynaptic depolarization. Anti-Hebbian LTP may occur in interneurons that are silent during periods of intense pyramidal cell firing, such as sharp waves, and lead to their altered activation during theta activity.Associative N-methyl-D-aspartate receptor (NMDAR)-dependent LTP is induced by coincident activity in afferent pathways sufficient to depolarize postsynaptic neurons (1). However, the voltage dependence of Ca 2+ -permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (CP-AMPARs) is opposite to that of NMDARs (2, 3). Because CP-AMPARs are blocked by cytoplasmic polyamines upon depolarization (4, 5), maximal Ca 2+ influx occurs when the membrane potential is relatively negative. LTP dependent on CP-AMPARs occurs in interneurons of the spinal cord and amygdala (6, 7), but its postsynaptic voltage dependence has not been explored. In hippocampal interneurons, CP-AMPARs have been implicated in long-term depression (8-10), and contribute to synaptic Ca 2+ transients, especially in the stratum oriens/alveus (11). Many interneurons in the oriens/alveus also show NMDAR-independent LTP (12). We therefore looked for associative LTP in these cells, while recording with the gramicidin perforated patch technique to preserve intracellular polyamines (13).Stimulation of pyramidal cell axon collaterals in the alveus evoked monosynaptic excitatory postsynaptic potentials (EPSPs) subthreshold for evoking action potentials. After recording a baseline, we paired high-frequency burst (HFB) stimulation (five pulses at 100 Hz, repeated 20 times) with stimulation of a second, supra-threshold, alveus pathway. "In-phase" associative pairing (phase difference ΔΦ = 0°) failed to elicit associative LTP in either pathway (n = 7; Fig. 1, A Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts two weak pathways, and then delivered HFBs to both pathways antiphase (ΔΦ = 180°). This evoked a persistent increase in EPSP initial slope in one or both pathways in all cells (n = 7; Fig. 1, C and D). LTP was elicited even when HFB stimuli were delivered to only one weak pathway (n = 7; Fig. 1, E and F). Thus, LTP at excitatory synapses on interneurons in the oriens/alveus is prevented by associative pairing, in direct contrast to NMDAR-dependent LTP (1).Can direct manipulation of the postsynaptic membrane potential similarly gate LTP induction? We delivered HFBs to one pathway coinciding with the trough (somatic voltage: −90 mV) of an imposed 4-Hz sinusoidal ...

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