A Nitric Oxide-Independent and β-Adrenergic Receptor-Sensitive Form of Metaplasticity Limits θ-Frequency Stimulation-Induced LTP in the Hippocampal CA1 Region

Abstract

The induction of long-term potentiation (LTP) and long-term depression (LTD) at excitatory synapses in the hippocampus can be strongly modulated by patterns of synaptic stimulation that otherwise have no direct effect on synaptic strength. Likewise, patterns of synaptic stimulation that induce LTP or LTD not only modify synaptic strength but can also induce lasting changes that regulate how synapses will respond to subsequent trains of stimulation. Collectively known as metaplasticity, these activity-dependent processes that regulate LTP and LTD induction allow the recent history of synaptic activity to influence the induction of activity-dependent changes in synaptic strength and may thus have an important role in information storage during memory formation. To explore the cellular and molecular mechanisms underlying metaplasticity, we investigated the role of metaplasticity in the induction of LTP by -frequency (5-Hz) synaptic stimulation in the hippocampal CA1 region. Our results show that brief trains of -frequency stimulation not only induce LTP but also activate a process that inhibits the induction of additional LTP at potentiated synapses. Unlike other forms of metaplasticity, the inhibition of LTP induction at potentiated synapses does not appear to arise from activity-dependent changes in NMDA receptor function, does not require nitric oxide signaling, and is strongly modulated by ␤-adrenergic receptor activation. Together with previous findings, our results indicate that mechanistically distinct forms of metaplasticity regulate LTP induction and suggest that one way modulatory transmitters may act to regulate synaptic plasticity is by modulating metaplasticity.

β-Adrenergic Receptor Activation Facilitates Induction of a Protein Synthesis-Dependent Late Phase of Long-Term Potentiation

“…Neuromodulatory transmitters play critical roles in regulating activity-dependent synaptic plasticity (Moody et al, 1999;Mann and Greenfield, 2003;van Dam et al, 2004). Neuromodulators such as noradrenaline can alter the sensitivity of LTP to electrical activity.…”

Cocaine-induced metaplasticity in the nucleus accumbens: Silent synapse and beyond

“…Among these, NMDAR-based metaplasticity, which can be either inhibitory or potentiating, at excitatory synapses has been most systemically examined. The inhibitory role of NMDAR-based metaplasticity was first demonstrated in the hippocampus, where it has been shown that low-level activity of NMDARs increases the induction threshold of subsequent LTP (Izumi et al, 1992; Larkman et al, 1992; Christie et al, 1995; Moody et al, 1999). This form of inhibitory metaplasticity seems to be mediated either by activation of the high affinity Ca 2+ -signaling, upregulation of the converging inhibitory synaptic input, or desensitization of LTP-associated molecular machineries (Davies et al, 1991; Komatsu, 1994; Chard et al, 1995; Malenka and Nicoll, 1999).…”

Norepinephrine triggers metaplasticity of LTP by increasing translation of specific mRNAs

“…Activity-dependent synaptic plasticity is a critical mechanism for learning and memory, and neuromodulatory transmitters play a vital role in regulating synaptic strength (Moody et al 1999;Mann and Greenfield 2003;van Dam et al 2004). Previous studies have found that when b-ARs are activated by ISO, maintenance of LTP is prolonged following a single train of HFS that, alone, is insufficient to elicit long-lasting potentiation (Gelinas and Nguyen 2005; see also Dahl and Li 1994 for dentate gyrus data).…”