Postsynaptic burst reactivation of hippocampal neurons enables associative plasticity of temporally discontiguous inputs

Fuchsberger, Tanja; Clopath, Claudia; Jarzebowski, Przemyslaw; Brzosko, Zuzanna; Wang, Hongbing; Paulsen, Ole

doi:10.7554/elife.81071

Cited by 13 publications

(8 citation statements)

References 87 publications

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“…Consistent with our previous results that burst-induced potentiation in the presence of dopamine requires postsynaptic PKA and protein synthesis (Fuchsberger et al, 2022), we found here that synaptic potentiation induced by low frequency synaptic stimulation in the presence of dopamine following a priming protocol, which would otherwise induce synaptic depression (Brzosko et al, 2015), also requires postsynaptic PKA and new protein synthesis. While conventional t-LTP remained intact, blocking protein synthesis in the postsynaptic neurons completely prevented DA-LTP, suggesting that dopamine induces the synthesis of plasticity-related proteins required for converting synaptic depression into potentiation.…”

Section: Discussionsupporting

confidence: 92%

“…We have recently reported that, in addition to synaptic activation, postsynaptic burst stimulation can also induce DA-LTP, which is mediated via the same AC-PKA signalling pathway and also requires protein synthesis (Fuchsberger et al, 2022). Synaptically induced DA-LTP develops gradually, while burst-induced DA-LTP shows rapid potentiation.…”

Section: Da-ltp Requires Cp-amparsmentioning

confidence: 99%

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Dopamine increases protein synthesis in hippocampal neurons enabling dopamine-dependent LTP

Fuchsberger,

Stockwell,

Woods

et al. 2024

Preprint

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The reward and novelty related neuromodulator dopamine plays an important role in hippocampal long-term memory, which is thought to involve protein synthesis-dependent synaptic plasticity. However, the direct effects of dopamine on protein synthesis, and the functional implications of newly synthesized proteins for synaptic plasticity, have not yet been investigated. We have previously reported that timing-dependent synaptic depression (t-LTD) can be converted into potentiation by dopamine application during synaptic stimulation (Brzsoko et al., 2015) or postsynaptic burst activation (Fuchsberger et al., 2022). Here we show that dopamine increases protein synthesis in mouse hippocampal CA1 neurons, enabling dopamine-dependent long-term potentiation (DA-LTP). We found that neuronal activity is required for the dopamine-induced increase in protein synthesis, which is mediated via the Ca2+-sensitive adenylate cyclase (AC) subtypes 1/8, cAMP, and cAMP-dependent protein kinase (PKA). Furthermore, dopamine induced a protein synthesis-dependent increase in the AMPA receptor subunit GluA1, but not GluA2. We found that DA-LTP is absent in GluA1 knock-out mice and that it requires calcium-permeable AMPA receptors. Taken together, our results suggest that dopamine together with neuronal activity controls synthesis of plasticity-related proteins, including GluA1, which enable DA-LTP via a signalling pathway distinct from that of conventional LTP.

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Section: Discussionsupporting

confidence: 92%

Section: Da-ltp Requires Cp-amparsmentioning

confidence: 99%

Dopamine increases protein synthesis in hippocampal neurons enabling dopamine-dependent LTP

Fuchsberger,

Stockwell,

Woods

et al. 2024

Preprint

Self Cite

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“…It shows that 1) BTSP drives the dynamics of hippocampal representations during familiarization, 2) the average probability of BTSP-triggering events is higher during novel experiences than familiar ones, especially in CA1, and the shape of the BTSP rule changes with familiarity in CA3. Novelty-dependent neuromodulatory and inhibitory signals (Pedrosa & Clopath, 2020; Sheffield et al, 2017) could mediate these changes by modulating both synaptic eligibility traces and the probability and duration of BTSP-triggering calcium plateaus (Fuchsberger et al, 2022; Magee & Grienberger, 2020).…”

Section: Discussionmentioning

confidence: 99%

BTSP, not STDP, Drives Shifts in Hippocampal Representations During Familiarization

Madar,

Dong,

Sheffield

2023

Preprint

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Synaptic plasticity is widely thought to support memory storage in the brain, but the rules determining impactful synaptic changes in-vivo are not known. We considered the trial-by-trial shifting dynamics of hippocampal place fields (PFs) as an indicator of ongoing plasticity during memory formation. By implementing different plasticity rules in computational models of spiking place cells and comparing to experimentally measured PFs from mice navigating familiar and novel environments, we found that Behavioral-Timescale-Synaptic-Plasticity (BTSP), rather than Hebbian Spike-Timing-Dependent-Plasticity, is the principal mechanism governing PF shifting dynamics. BTSP-triggering events are rare, but more frequent during novel experiences. During exploration, their probability is dynamic: it decays after PF onset, but continually drives a population-level representational drift. Finally, our results show that BTSP occurs in CA3 but is less frequent and phenomenologically different than in CA1. Overall, our study provides a new framework to understand how synaptic plasticity shapes neuronal representations during learning.

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“…The copyright holder for this preprint this version posted June 30, 2023. ; https://doi.org/10.1101/2023.06.29.547097 doi: bioRxiv preprint input 12,13,59 and; 2) BTSP, where the pairing of temporally discontiguous pre-and postsynaptic activation induces synaptic potentiation 17 . In the former case, the genesis of eligibility traces per se is conjunctive in nature since it relies on both pre-and postsynaptic events, a hallmark of STDP protocols.…”

Section: Discussionmentioning

confidence: 99%

“…Protracted eligibility traces would thereby allow individual neurons to solve the temporal credit assignment problem by binding cues that are separated by behaviorally relevant temporal delays. An emerging literature is beginning to identify forms of synaptic plasticity that exhibit temporal features that are consistent with the existence of a neural correlate of eligibility traces 12,13,14,15,16,10 . In particular, important recent work in the hippocampus has outlined the presence of a novel form of synaptic plasticity, termed Behavioral Timescales Synaptic Plasticity (BTSP), that emerges following the pairing of synaptic and cellular events that are separated by up to ~ 2 seconds 17,18,19 .…”

Section: Mainmentioning

confidence: 99%

Cellular Substrate of Eligibility Traces

Caya-Bissonnette

Naud

Béı̈que

2023

Preprint

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The ability of synapses to undergo associative, activity-dependent weight changes constitutes a linchpin of current cellular models of learning and memory. It is, however, unclear whether canonical forms of Hebbian plasticity, which inherently detect correlations of cellular events occurring over short time scales, can solve the temporal credit assignment problem proper to learning driven by delayed behavioral outcomes. Recent evidence supports the existence of synaptic eligibility traces, a time decaying process that renders synapses momentarily eligible for a weight update by a delayed instructive signal. While eligibility traces offer a means of retrospective credit assignment, their material nature is unknown. Here, we combined whole-cell recordings with two-photon uncaging, calcium imaging and biophysical modeling to address this question. We observed and parameterized a form of behavioral timescale synaptic plasticity (BTSP) in layer 5 pyramidal neurons of mice prefrontal areas wherein the pairing of temporally separated pre- and postsynaptic events (0.5 s to 1 s), irrespective of order, induced synaptic potentiation. By imaging calcium in apical oblique dendrites, we reveal a short-term and associative plasticity of calcium dynamics (STAPCD) whose time-dependence mirrored the induction rules of BTSP. We identified a core set of molecular players that were essential for both STAPCD and BTSP and that, together with computational simulations, support a model wherein the dynamics of intracellular handling of calcium by the endoplasmic reticulum (ER) provides a latent memory trace of neural activity that instantiates synaptic weight updates upon a delayed instructive signal. By satisfying the requirements expected of eligibility traces, this mechanism accounts for how individual neurons can conjunctively bind cellular events that are separated by behaviorally relevant temporal delays, and thus offers a cellular model of reinforced learning.

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Postsynaptic burst reactivation of hippocampal neurons enables associative plasticity of temporally discontiguous inputs

Cited by 13 publications

References 87 publications

Dopamine increases protein synthesis in hippocampal neurons enabling dopamine-dependent LTP

Dopamine increases protein synthesis in hippocampal neurons enabling dopamine-dependent LTP

BTSP, not STDP, Drives Shifts in Hippocampal Representations During Familiarization

Cellular Substrate of Eligibility Traces

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