Acute Suppression of Spontaneous Neurotransmission Drives Synaptic Potentiation

Abstract

The impact of spontaneous neurotransmission on neuronal plasticity remains poorly understood. Here, we show that acute suppression of spontaneous N-methyl-D-aspartate (NMDA) receptor-mediated neurotransmission potentiates synaptic responses in the CA1 regions of rat and mouse hippocampus. This potentiation requires protein synthesis, brain-derived neurotrophic factor (BDNF) expression, eukaryotic elongation factor-2 kinase (eEF2K) function and increased surface expression of 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA) receptors. Our behavioral studies link this same synaptic signaling pathway to the fast-acting antidepressant responses elicited by ketamine. We also show that selective neurotransmitter depletion from spontaneously recycling vesicles triggers synaptic potentiation via the same pathway as NMDA receptor blockade, demonstrating that presynaptic impairment of spontaneous release, without manipulation of evoked neurotransmission, is sufficient to elicit postsynaptic plasticity. These findings uncover an unexpectedly dynamic impact of spontaneous glutamate release on synaptic efficacy and provide new insight into a key synaptic substrate for rapid antidepressant action.

Observation of Distressed Conspecific as a Model of Emotional Trauma Generates Silent Synapses in the Prefrontal-Amygdala Pathway and Enhances Fear Learning, but Ketamine Abolishes those Effects

“…Normalization of AMPAR/NMDAR ratio and elimination of silent synapses by ketamine are consistent with findings that ketamine increases AMPAR/NMDAR ratio and enhances Emotional trauma generates silent synapses W Ito et al surface expression of AMPAR (Maeng et al, 2008;Nosyreva et al, 2013;Tizabi et al, 2012). However, we did not detect increases in AMPAR/NMDAR in control mice injected with ketamine.…”

“…The reason for the discrepancy could be the timing of our measures. The reported increases were detected within minutes after single ketamine injection (Maeng et al, 2008;Nosyreva et al, 2013) or after 10 days of repeated injections (Tizabi et al, 2012), whereas our recordings were done 24 h after injection. While the network process leading to the formation of silent synapses after OF remains to be determined, a desynchronized neuronal activity has been shown to increase the number of AMPAR-silent synapses (Huupponen et al, 2013).…”

“…Evidence that ketamine increases AMPAR over NMDAR function (Maeng et al, 2008;Nosyreva et al, 2013;Tizabi et al, 2012) predicts that ketamine counters the effects from OF. Mice were injected with ketamine (10 mg/kg) or saline immediately after OF, followed by the PA training on the next day.…”

Possible contributions of a novel form of synaptic plasticity inAplysiato reward, memory, and their dysfunctions in mammalian brain

“…Recent studies in several species have shown that spontaneous release also contributes to other synaptic effects, including some cases of homeostatic scaling (Sutton et al 2004(Sutton et al , 2006(Sutton et al , 2007Frank et al 2006Frank et al , 2009Dickman and Davis 2009;Zhang et al 2009;Lee et al 2010;Nosyreva et al 2013). Scaling in those cases has additional similarities to intermediate-and long-term facilitation in Aplysia: Both types of plasticity can involve postsynaptic Ca 2+ , protein synthesis, AMPA receptor insertion, and modulation of the presynaptic probability of release.…”

“…2A, 3, 4;Huang and Kandel 1995;Hyman et al 2006;Lemon and Manahan-Vaughan 2006;Navakkode et al 2007;Bailey et al 2008). Spontaneous EPSPs are often thought to be insufficient to activate NMDA receptors, but there is growing evidence that they can even at rest (Sutton et al 2006(Sutton et al , 2007Espinosa and Kavalali 2009;Autry et al 2011;Povysheva and Johnson 2012;Nosyreva et al 2013). Furthermore, when spontaneous release is enhanced by a modulatory transmitter, in some cases the EPSPs can summate enough in the postsynaptic dendrites to reach threshold for firing (e.g., Sharma and Vijayaraghavan 2003).…”