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Synapse-specific connectivity and dynamics determine microcircuit function but are challenging to explore with classic paired recordings due to their low throughput. We therefore implemented optomapping, a ∼100-fold faster two-photon optogenetic method. In mouse primary visual cortex (V1), we optomapped 30,454 candidate inputs to reveal 1,790 excitatory inputs to pyramidal, basket, and Martinotti cells. Across these cell types, log-normal distribution of synaptic efficacies emerged as a principle. For pyramidal cells, optomapping reproduced the canonical circuit but unexpectedly uncovered that the excitation of basket cells concentrated to layer 5 and that of Martinotti cells dominated in layer 2/3. The excitation of basket cells was stronger and reached farther than the excitation of pyramidal cells, which may promote stability. Short-term plasticity surprisingly depended on cortical layer in addition to target cell. Finally, optomapping revealed an overrepresentation of shared inputs for interconnected layer-6 pyramidal cells. Thus, by resolving the throughput problem, optomapping uncovered hitherto unappreciated principles of V1 structure., Competing Interests: The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication., (© 2024 The Author(s).)

Short-term plasticity is an important feature in the brain for shaping neural dynamics and for information processing. Short-term plasticity is known to depend on many factors including brain region, cortical layer, and cell type. Here we focus on vasoactive-intestinal peptide (VIP) interneurons (INs). VIP INs play a key disinhibitory role in cortical circuits by inhibiting other IN types, including Martinotti cells (MCs) and basket cells (BCs). Despite this prominent role, short-term plasticity at synapses to and from VIP INs is not well described. In this study, we therefore characterized the short-term plasticity at inputs and outputs of genetically targeted VIP INs in mouse motor cortex. To explore inhibitory to inhibitory (I → I) short-term plasticity at layer 2/3 (L2/3) VIP IN outputs onto L5 MCs and BCs, we relied on a combination of whole-cell recording, 2-photon microscopy, and optogenetics, which revealed that VIP IN→MC/BC synapses were consistently short-term depressing. To explore excitatory (E) → I short-term plasticity at inputs to VIP INs, we used extracellular stimulation. Surprisingly, unlike VIP IN outputs, E → VIP IN synapses exhibited heterogeneous short-term dynamics, which we attributed to the target VIP IN cell rather than the input. Computational modeling furthermore linked the diversity in short-term dynamics at VIP IN inputs to a wide variability in probability of release. Taken together, our findings highlight how short-term plasticity at VIP IN inputs and outputs is specific to synapse type. We propose that the broad diversity in short-term plasticity of VIP IN inputs forms a basis to code for a broad range of contrasting signal dynamics., Competing Interests: AA was employed by MTL.AI Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 McFarlan, Gomez, Chou, Alcolado, Costa and Sjöström.)

Hebb postulated that, to store information in the brain, assemblies of excitatory neurons coding for a percept are bound together via associative long-term synaptic plasticity. In this view, it is unclear what role, if any, is carried out by inhibitory interneurons. Indeed, some have argued that inhibitory interneurons are not plastic. Yet numerous recent studies have demonstrated that, similar to excitatory neurons, inhibitory interneurons also undergo long-term plasticity. Here, we discuss the many diverse forms of long-term plasticity that are found at inputs to and outputs from several types of cortical inhibitory interneuron, including their plasticity of intrinsic excitability and their homeostatic plasticity. We explain key plasticity terminology, highlight key interneuron plasticity mechanisms, extract overarching principles and point out implications for healthy brain functionality as well as for neuropathology. We introduce the concept of the plasticitome - the synaptic plasticity counterpart to the genome or the connectome - as well as nomenclature and definitions for dealing with this rich diversity of plasticity. We argue that the great diversity of interneuron plasticity rules is best understood at the circuit level, for example as a way of elucidating how the credit-assignment problem is solved in deep biological neural networks., (© 2022. Springer Nature Limited.)

Presynaptic NMDA receptors (preNMDARs) control synaptic release, but it is not well understood how. Rab3-interacting molecules (RIMs) provide scaffolding at presynaptic active zones and are involved in vesicle priming. Moreover, c-Jun N-terminal kinase (JNK) has been implicated in regulation of spontaneous release. We demonstrate that, at connected layer 5 pyramidal cell pairs of developing mouse visual cortex, Mg 2+ -sensitive preNMDAR signaling upregulates replenishment of the readily releasable vesicle pool during high-frequency firing. In conditional RIM1αβ deletion mice, preNMDAR upregulation of vesicle replenishment was abolished, yet preNMDAR control of spontaneous release was unaffected. Conversely, JNK2 blockade prevented Mg 2+ -insensitive preNMDAR signaling from regulating spontaneous release, but preNMDAR control of evoked release remained intact. We thus discovered that preNMDARs signal differentially to control evoked and spontaneous release by independent and non-overlapping mechanisms. Our findings suggest that preNMDARs may sometimes signal metabotropically and support the emerging principle that evoked and spontaneous release are distinct processes. VIDEO ABSTRACT., (Copyright © 2017 Elsevier Inc. All rights reserved.)