Behavioral timescale synaptic plasticity (BTSP) is a form of single-shot learning observed in hippocampal place cells in mice (Bittner et al., 2015, 2017). The idea is that post-synaptic activations (“eligibility traces”) are potentiated by a dendritic plateau potential/burst (“instructive signal”) that comes up to several seconds after the first signal. This result turned out to be one of the most reproducible findings of recent systems neuroscience, being replicable across labs and across stimulation protocols (via single-cell electrophysiology (Bittner et al., 2015) but also via optogenetic induction (O’Hare et al., 2022)). Many different labs are working in this interesting field, and here are a few recent papers on this topic.

A role for CaMKII in BTSP

Xiao et al. (2023) from the Magee lab report on a “critical role for CaMKII” in BTSP. “CaMKII” is known as a promotor fragment that is specific for excitatory neurons, but CaMKII is more than that – CaMKII is a calcium-dependent kinase (but see the recent paper by Tullis et al. (2023)) with important functions for plasticity. After phosphorylation, CaMKII remains in this activated state for several seconds and is therefore a candidate actor for BTSP, which acts on a timescale of several seconds as well. I learnt from this paper’s introduction that there is a CaMKII sensor based on FRET which revealed a shorter decay time for CaMKII’s phosphorylated state when it carried a specific mutation in CaMKII.

The authors take advantage of an established mouse line with this specific mutation, which resulted in deficits of memory and synaptic plasticity. Xiao et al. found, using in vivo patch clamp, that BTSP was prevented or reduced in these mutated mice (Fig. 3), suggesting an indeed critical role of CaMKII for the induction of BTSP.

As a side-finding, the authors describe that intrinsic burst propensities of CA1 neurons were quite different for mutants and wildtypes (unfortunately, they only show few example traces of such bursts), and they follow up on this result by characterizing the intrinsic properties in slices.
A question that came up and was partially addressed by the authors are the possible side-effects of chronically mutated CaMKII on the entire development and on other brain regions or also the hippocampus before the start of the experiment. However, the main finding of the manuscript (prevention of BTSP in CaMKII-mutated mice) seems to be solid despite these non-avoidable confounds. Of course, the study does not address how exactly CaMKII is involved in BTSP. The way to address this question will probably require using fluorescent reporters of CaMKII activity and very tedious dissection of molecular signaling pathways.

Monitoring of place cell induction via BTSP with calcium imaging

Grienberger and Magee (2022) conducted a simple and elegant study using calcium imaging that confirms and connects previous ideas on hippocampal plasticity and BTSP.
It had been known since a long time that hippocampal place cells are more abundant around more important locations, for example, reward locations. Here, the authors observe the transition from similar representation of all locations towards preferred representation of reward location using calcium imaging. They find evidence that this transition is induced by BTSP. To this end, they identify putative BTSP burst events in single neurons from calcium imaging data and track the activities of these neurons before and after such burst events. Moreover, they use optogenetics to show that input from entorhinal cortex (EC3) is required for the transformation of equal to reward-preferring representation of space. This finding is in line with the existing ideas about EC3 projections to provide the instructive signal that triggers bursts in apical dendrites and BTSP in CA1 neurons.

One of the most critical parts of this study is the identification of bursts to induce place fields using calcium imaging (in previous studies, this was usually done by in vivo whole-cell recordings). There is some uncertainty about the identification of these induction events (see the “CA1 place cell identification” subsection in the Methods section; check out a more recent preprint by the same lab, which uses much more complex criteria to detect BTSP events from calcium imaging; see the Methods subsection “BTSP Analysis” from  Vaidya et al. (2023)). It would be very interesting to thoroughly study – for example with simultaneous calcium imaging and single-cell electrophysiology in vivo -, which calcium events correspond to BTSP/burst events and which calcium events correspond to “regular” spiking. However, this seems technically too challenging, and the more ad-hoc methods to identify such events in this study seem fully adequate for the question addressed. P.S. If you find this paper interesting, check out the publicly available reviewer reports.

Voltage imaging of BTSP with optogenetic perturbations

Fan et al. (2023) use an impressive combination of voltage imaging and optogenetics techniques in vivo to study BTSP. Let me cite the abstract to give an idea about the methodological craziness of this study: “We combined genetically targeted voltage imaging with targeted optogenetic activation and silencing of pre- and post-synaptic neurons to study the mechanisms underlying hippocampal behavioral timescale plasticity.” Optogenetic induction of place cells in hippocampus has been done before, but not combined with voltage imaging. This together with simultaneous silencing of specific projections sounds like a completely crazy project. Several interesting findings: Excitability of pyramidal neurons (as measured with combined optogenetic activation and voltage imaging) did not increase upon BTSP. CA2/3 to CA1 inputs were potentiated upon BTSP (optogenetic activation of, although only contralateral, CA2/3 with a fiber during voltage imaging of CA1 neurons). And the activity of CA2/3 cells projecting to CA1 was required for BTSP (optogenetic silencing of projection-specific CA2/3 neurons while voltage imaging in CA1).

Overall, I would have loved to read more about these experiments and their interpretation.
Grienberger and Magee (2022) showed that (ipsilateral) EC3 input is necessary for BTSP, while Fan et al. (2023) showed that (contralateral) CA2/3 input is required. The idea is that both CA2/3 (for the eligibility trace) and EC3 input (for the instructive signal) are required, and both results are consistent with the standard theory of BTSP. It is only a bit surprising that even the contralateral CA2/3 input, as reported by Fan et al. was sufficient. In their study, the contralateral side was inhibited to enable fiber placement at CA2/3 and voltage imaging in CA1. This must be kept in mind because the authors, to access CA1 with 1P voltage imaging, also removed the central part of the external capsule; I wonder whether this removed part of the corpus callosum does not contain some of these contralateral projections.

A plasticity rule in cortex reminiscent of BTSP

Caya-Bissonnette et al. (2023) from Jean-Claude Béïque’s lab in Ottawa used slice physiology and modeling to show that a variant of BTSP exists in layer 5 pyramidal cells of cortex (S1) in mice. I have to admit that the often very long and complicated sentences in the Results section and the slightly overcrowded figures make it a tough paper to read, but it is worth it.

The authors use pre- and post-synaptic stimulation pairing paradigms as they were used extensively since the 1990s – but with the crucial difference that pre- and post-synaptic events were not separated by milliseconds but by 0.5-1.0 s. Using this approach, they found a potentiation of synapses that did not depend on the temporal order of pre/post stimulation. Therefore, they call this plasticity rule “associative”. The authors furthermore show that the endoplasmic reticulum (ER, reminiscent of O’Hare et al. (2022)) and several related calcium signaling pathways are involved in the latent “eligibility trace” that holds the memory of first stimulation before the second stimulation arrives, by extending the decay time constant of calcium (Fig. 4). The decay time is not extended by much, but maybe this slight increase is enough to induce plasticity.

Altogether, this is a very interesting study focusing on slice physiology. On one side, this is a limitation since the paper claims to have found a cortical variant of hippocampal BTSP, an effect that was primarily convincing because it had been shown in behaving animals. Therefore, one should critically inspect the choices of the plasticity protocol. For example, I noticed that the authors used a 10×20 Hz stimulation that seemed to me maybe a bit too strong and repetitive a stimulation and does not resemble typical BTSP events in vivo; moreover, during BTSP events, bursting and the associated plateau potentials were shown to be involved in the post-synaptic not the pre-synaptic cell in vivo (Bittner et al., 2015). Maybe I missed it, but I did not find this aspect discussed in the paper.

On the other side, the study is, despite this limitation, very interesting since it demonstrates how powerful slice physiology can be and how much we miss by only focusing on processes accessible in vivo. Moreover, it shows under which condition a classical STDP protocol can be transformed into a longer-timescale “BTSP” (Fig. 1F). To my knowledge, a plasticity rule with such long delays has not been convincingly demonstrated in cortex before, neither in slices nor in vivo. It may be a stretch to call the observed effect “BTSP”, drawing the analogy to the results seen in hippocampus in vivo, thereby gradually diluting the meaning of “BTSP”. However, this is just naming conventions – the science in the paper is interesting.

That’s it from my side about interesting papers on behavioral timescale synaptic plasticity.

Did I miss an interesting recent paper on this topic? Let me know in the comments!

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References:

Bittner, K.C., Grienberger, C., Vaidya, S.P., Milstein, A.D., Macklin, J.J., Suh, J., Tonegawa, S., Magee, J.C., 2015. Conjunctive input processing drives feature selectivity in hippocampal CA1 neurons. Nat. Neurosci. 18, 1133–1142. https://doi.org/10.1038/nn.4062

Bittner, K.C., Milstein, A.D., Grienberger, C., Romani, S., Magee, J.C., 2017. Behavioral time scale synaptic plasticity underlies CA1 place fields. Science 357, 1033–1036. https://doi.org/10.1126/science.aan3846

Caya-Bissonnette, L., Naud, R., Béïque, J.-C., 2023. Cellular Substrate of Eligibility Traces. https://doi.org/10.1101/2023.06.29.547097

Fan, L.Z., Kim, D.K., Jennings, J.H., Tian, H., Wang, P.Y., Ramakrishnan, C., Randles, S., Sun, Y., Thadhani, E., Kim, Y.S., Quirin, S., Giocomo, L., Cohen, A.E., Deisseroth, K., 2023. All-optical physiology resolves a synaptic basis for behavioral timescale plasticity. Cell 186, 543-559.e19. https://doi.org/10.1016/j.cell.2022.12.035

Grienberger, C., Magee, J.C., 2022. Entorhinal cortex directs learning-related changes in CA1 representations. Nature 611, 554–562. https://doi.org/10.1038/s41586-022-05378-6

O’Hare, J.K., Gonzalez, K.C., Herrlinger, S.A., Hirabayashi, Y., Hewitt, V.L., Blockus, H., Szoboszlay, M., Rolotti, S.V., Geiller, T.C., Negrean, A., Chelur, V., Polleux, F., Losonczy, A., 2022. Compartment-specific tuning of dendritic feature selectivity by intracellular Ca2+ release. Science 375, eabm1670. https://doi.org/10.1126/science.abm1670

Tullis, J.E., Larsen, M.E., Rumian, N.L., Freund, R.K., Boxer, E.E., Brown, C.N., Coultrap, S.J., Schulman, H., Aoto, J., Dell’Acqua, M.L., Bayer, K.U., 2023. LTP induction by structural rather than enzymatic functions of CaMKII. Nature 621, 1–8. https://doi.org/10.1038/s41586-023-06465-y

Vaidya, S.P., Chitwood, R.A., Magee, J.C., 2023. The formation of an expanding memory representation in the hippocampus. https://doi.org/10.1101/2023.02.01.526663

Xiao, K., Li, Y., Chitwood, R.A., Magee, J.C., 2023. A critical role for CaMKII in behavioral timescale synaptic plasticity in hippocampal CA1 pyramidal neurons. https://doi.org/10.1101/2023.04.18.537377