Peer review of: Interneuron-specific plasticity at parvalbumin and somatostatin inhibitory synapses onto (2019)

Reviewers' Comments: 
 
Reviewer #1: 
Remarks to the Author: 
Udakis et al. describe interneuron-specific forms of inhibitory synaptic plasticity in hippocampus, which 
contributes to modulation of the excitation of CA1 pyramidal cells. In their paradigm, TBS stimulation 
of PV or SST axons induces long-term depression of the PV synaptic inputs, and long-term 
potentiation of SST synaptic inputs, respectively. PV-iLTD and SST-iLTP can also be induced using 
STDP pairing, with strong effects at 0ms delays. Using pharmacology, the authors determine that the 
iLTD is dependent on T-type calcium channels and a calcineurin-mediated pathway, and iLTP on both 
T-type and L-type calcium channels and a CaMKII-dependent pathway. Based on previously described 
innervation patterns suggesting that PV cells predominantly inhibit perisomatic dendrites (through 
feed forward inhibition) and SST cells distal dendrites (through feedback inhibition), the authors derive 
a multicompartmental model for plasticity in which the changes in PV and SST interneuron inputs 
modulate Schaffer collateral and temporammonic pathway-mediated activity of pyramidal cells, 
respectively. Further modeling experiments then clearly lend support to the hypothesis that these 
forms of plasticity explain the stability of place cell activity. 
 
This paper describes a novel form of differential inhibitory synaptic plasticity in hippocampus with 
strong implications (and a possible explanation) for place cell plasticity and stability. I consider these 
important new insights and support publication. The model provides a nice framework for further 
experimental testing. 
 
I have two points that I think need to be addressed before publication. 
 
Major points: 
 
1. I find it difficult to comprehend what is being stimulated in the control pathway. The authors 
mention that they are recording IPSCs upon electrical stimulation of inputs in the pyramidal cell layer 
or stratum radiatum. But isn’t a large fraction of the inhibitory inputs in these regions exactly derived 
from the inputs they are testing? So, I find it a bit puzzling that the consecutive E-L and L-E pulse 
experiment in Suppl. Fig 1h remains unaffected. I don’t doubt the outcome of the experiments, but 
perhaps the authors could comment on why they think this is the case. Does it have to do with a 
limited number of inputs that are labeled with channelrhodopsin vs what is recruited through electrical 
stimulation (i.e. the monopolar stimulating electrode could cause wide spread activation of synapses – 
even beyond the targeted pathways). 
 
2. It is also not clear to me how the TBS results (Fig 1) link to the STDP results (Fig 2). What would be 
the induction mechanism in the TBS experiments, in which the cells are held a 0mV and glutamate 
receptors are blocked? Do the authors think that the mechanisms are similar to the STDP paradigm? I 
find this somewhat puzzling, as the authors state that iSTDP depended on T-type calcium channels, 
which require hyperpolarization for de-inactivation. Would this happen in a neuron held at 0 mV? 
 
Minor points. 
3. Out of curiosity. Do the authors think that the -60ms pairing-induced SST-iLTD depends on the 
same mechanism as PV-iLTD; and would this be similar to the PV-iLTD at 0ms? 
 
4. Weren’t the authors surprised that SST-iLTP required the activation of CAMKII, which normally 
requires a strong depolarization? Do bAPs travel far enough into the distal dendrites to cause such a 
strong depolarization? Perhaps the authors could elaborate a bit on this in the discussion section. 
 

5. It would be helpful to indicate in the graphs over which periods the data were averaged to plot the 
‘before’ and ‘after’ plasticity-histograms. 
 
 
 
Reviewer #2: 
Remarks to the Author: 
The manuscript by Udakis et al explores the induction requirements and possible circuit consequences 
of plasticity at interneuron synapses on pyramidal neurons in hippocampal CA1. The study ranges 
widely, from optogenetic and pharmacological manipulations in vitro to a computational model of how 
plasticity of feed-forward inhibition of temporoammonic and Schaffer collateral inputs could contribute 
to stabilizing place cells. The study is interesting although there are gaps in the evidence linking the 
different parts of the work. 
1. Fig. 1 shows convincing and abrupt changes in IPSC amplitude in opposite directions following 
optogenetic TBS, but the rest of the data using spike-timing protocols show variable and slow changes 
in IPSCs. Why? 
2. It is curious that the control pathway went in opposite directions in the experiments reported in Fig. 
1. 
3. The authors apply repeated t-tests when comparing various manipulations (pharmacology, different 
timing protocols), and do not take into account multiple comparisons. An ANOVA would be more 
appropriate, although the experiments may have been underpowered. 
4. The authors use absence of significance to argue for no effect, which is not correct. 
5. The involvement of T-type channels is inferred on the basis of pharmacology, but the authors do 
not show how the different protocols may have led to different degrees of Ca2+ influx via these 
channels, either with membrane voltage or intracellular Ca2+ recordings or simulations. 
6. The near-threshold action potential trains reported in Fig. 7 are interesting and the effects of iLTP 
induction at PV vs SST synapses are striking. However, I am very puzzled how the authors obtained 
trains of spikes when stimulating the temporoammonic input. Several previous papers report that this 
only leads to very large IPSPs because feed-forward inhibition swamps any direct excitation of the 
pyramidal neuron dendrites. 
7. Given the profound short-term depression seen at PV interneuron synapses, I would expect to see 
markedly different effects of iLTD on early vs late spikes in the 10-spike trains. 
8. The authors do not actually show that i-LTP/i-LTD has been induced in these experiments. This 
should be possible. Indeed, it might even be possible to show how optogenetic induction of plasticity 
alters disynaptic IPSPs evoked by the electrical stimuli.