Creation of AMPA-silent synapses in the neonatal hippocampus

Xiao, Min-Yi; Wasling, Pontus; Hanse, Eric; Gustafsson, Bengt

doi:10.1038/nn1196

Cited by 108 publications

(134 citation statements)

References 47 publications

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“…Our suggested low state may also include ''silent'' synapses in which no ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-based synaptic currents are detectable (32). Exploring this possibility in the future will require recording conditions and animal ages that permit identification of silent synapses or the induction of silencing (33).…”

Section: Discussionmentioning

confidence: 99%

Graded bidirectional synaptic plasticity is composed of switch-like unitary events

O’Connor

Wittenberg

Wang

2005

Proc. Natl. Acad. Sci. U.S.A.

218

210

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Biological information storage events are often rapid transitions between discrete states. In neural systems, the initiation of bidirectional plasticity by all-or-none events may help confer robustness on memory storage. Here, we report that at CA3-CA1 hippocampal synapses, individual potentiation and depression plasticity events are discrete and heterogeneous in nature. Individual synapses began from extreme high and low strength states. Unitary plasticity events were all-or-none and drove synaptic strength between extremes in <1 min. Under naïve conditions, approximately three-fourths of synapses began in a low-strength state. The timing of these unitary events can account for the time course of macroscopic synaptic plasticity.B oth increases (long-term potentiation, LTP) (1) and decreases (long-term depression, LTD) in synaptic strength are almost always measured macroscopically across populations of synaptic contacts (2). Macroscopic recordings, in which plasticity appears as a graded phenomenon, have ranged from extracellular recordings from many thousands of synapses (3, 4) to single-cell recordings (5), including recordings from connected pairs of nearby single neurons representing summed activity from order 10 synaptic terminals (6, 7).Plasticity has been described in terms of transitions among distinct states (7). However, the concept of synaptic states has not been explored in terms of unitary synaptic strength. Characterizing plasticity at this level requires observations from putative single terminals.An attractive system for studying unitary plasticity events is the hippocampal CA3-CA1 pathway (4, 8), where connected CA3 and CA1 neurons communicate typically by a single synaptic contact (9). Minimal stimulation techniques (10-12) allow plasticity transitions to be localized in time as they occur (13). Previous work (13) indicates that unitary synaptic potentiation, at least in its initial stages, may be an all-or-none event.Here, we report on the unitary properties of the initiation of potentiation and depression at CA3-CA1 synapses. We find that both potentiation and depression events are all-or-none and sudden. These events can be reconstituted to account for the time course of plasticity on a macroscopic scale. MethodsSlice Preparation. Transverse hippocampal slices (300 m) from Sprague-Dawley rats (postnatal day 13-21) were cut in ice-cold artificial cerebrospinal fluid (ACSF) comprising (in mM) 126 NaCl, 3 KCl, 1 NaH 2 PO 4 , 25 D-glucose, 25 NaHCO 3 , 2 CaCl 2 , and 1 MgCl 2 saturated with 95% O 2 ͞5% CO 2 , incubated at 34°C for 10-15 min, and transferred to a room-temperature interface chamber for Ն60 min before recording. The cutting angle was such that excitatory postsynaptic current (EPSC) size in response to stimulation of stratum radiatum decreased rapidly as the stimulation electrode was moved toward CA3. By using this cutting angle and moving the stimulation electrode as far toward CA3 as possible, we reduced the likelihood of stimulating multiple connected axons. For recordings, slic...

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Section: Discussionmentioning

confidence: 99%

Graded bidirectional synaptic plasticity is composed of switch-like unitary events

O’Connor

Wittenberg

Wang

2005

Proc. Natl. Acad. Sci. U.S.A.

218

210

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“…Furthermore, overexpression of GluA2 subunits increases dendritic spines (Passafaro et al, 2003), indicating that AMPARs have a critical role in synaptogenesis. Moreover, in young hippocampal slices, a set of excitatory synapses that are originally detected as AMPAR-present synapses become NMDAR-only synapses after a few trials of weak activations (Xiao et al, 2004). These and other results lead to the hypothesis that AMPARs are present but are highly labile at nascent synapses and that they become AMPAR-silent synapses upon modest activity (Groc et al, 2006).…”

Section: Mechanisms Underlying Generation and Maturation Of Silent Symentioning

confidence: 92%

Cocaine-Induced Synaptic Alterations in Thalamus to Nucleus Accumbens Projection

Neumann

Wang

Yan

et al. 2016

Neuropsychopharmacol

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Exposure to cocaine induces addiction-associated behaviors partially through remodeling neurocircuits in the nucleus accumbens (NAc). The paraventricular nucleus of thalamus (PVT), which projects to the NAc monosynaptically, is activated by cocaine exposure and has been implicated in several cocaine-induced emotional and motivational states. Here we show that disrupting synaptic transmission of select PVT neurons with tetanus toxin activated via retrograde trans-synaptic transport of cre from NAc efferents decreased cocaine selfadministration in rats. This projection underwent complex adaptations after self-administration of cocaine (0.75 mg/kg/infusion; 2 h/d × 5 d, 1 d overnight training). Specifically, 1d after cocaine self-administration, we observed increased levels of AMPA receptor (AMPAR)-silent glutamatergic synapses in this projection, accompanied by a decreased ratio of AMPAR-to-NMDA receptor (NMDAR)-mediated EPSCs. Furthermore, the decay kinetics of NMDAR EPSCs was significantly prolonged, suggesting insertion of new GluN2B-containing NMDARs to PVT-to-NAc synapses. After 45-d withdrawal, silent synapses within this projection returned to the basal levels, accompanied by a return of the AMPAR/NMDAR ratio and NMDAR decay kinetics to the basal levels. In amygdala and infralimbic prefrontal cortical projections to the NAc, a portion of cocaine-generated silent synapses becomes unsilenced by recruiting calcium-permeable AMPARs (CP-AMPARs) after drug withdrawal. However, the sensitivity of PVT-to-NAc synapses to CP-AMPAR-selective antagonists was not changed after withdrawal, suggesting that CP-AMPAR trafficking is not involved in the evolution of cocaine-generated silent synapses within this projection. Meanwhile, the release probability of PVT-to-NAc synapses was increased after short-and long-term cocaine withdrawal. These results reveal complex and profound alterations at PVT-to-NAc synapses after cocaine exposure and withdrawal.

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“…Also, while the success rate of AMPA EPSCs was lower than NMDA EPSCs in WT mice, indicative of postsynaptically silent synapses within the activated synapse population, no corresponding difference was observed in GluA4 -/-mice at this developmental stage (P4-P8). One possible explanation is that GluA4 also contributes to the depression of AMPAR-mediated transmission in response to asynchronous activity at very young synapses (Xiao et al, 2004;Hanse et al, 2009). Thus, the absence of GluA4 may result in premature stabilization of AMPAR-mediated transmission at certain synapses.…”

Section: Physiological Significance Of Glua4-dependent Plasticity In mentioning

confidence: 99%

Molecular mechanisms controlling synaptic recruitment of GluA4 subunit-containing AMPA-receptors critical for functional maturation of CA1 glutamatergic synapses

et al. 2017

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Synaptic recruitment of AMPA receptors (AMPARs) represents a key postsynaptic mechanism driving functional development and maturation of glutamatergic synapses. At immature hippocampal synapses, PKA-driven synaptic insertion of GluA4 is the predominant mechanism for synaptic reinforcement. However, the physiological significance and molecular determinants of this developmentally restricted form of plasticity are not known. Here we show that PKA activation leads to insertion of GluA4 to synaptic sites with initially weak or silent AMPAR-mediated transmission. This effect depends on a novel mechanism involving the extreme C-terminal end of GluA4, which interacts with the membrane proximal region of the C-terminal domain to control GluA4 trafficking. In the absence of GluA4, strengthening of AMPAR-mediated transmission during postnatal development was significantly delayed. These data suggest that the GluA4-mediated activation of silent synapses is a critical mechanism facilitating the functional maturation of glutamatergic circuitry during the critical period of experience-dependent fine-tuning.

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Creation of AMPA-silent synapses in the neonatal hippocampus

Cited by 108 publications

References 47 publications

Graded bidirectional synaptic plasticity is composed of switch-like unitary events

Graded bidirectional synaptic plasticity is composed of switch-like unitary events

Cocaine-Induced Synaptic Alterations in Thalamus to Nucleus Accumbens Projection

Molecular mechanisms controlling synaptic recruitment of GluA4 subunit-containing AMPA-receptors critical for functional maturation of CA1 glutamatergic synapses

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