Biology subjects

Sjostrom, P. J.

Publications and source records attributed to Sjostrom, P. J..

4 recordsLinked to original sources

bioRxiv2026

Layer-5 Pyramidal Cell tLTD Requires Astrocytic Ca2+ and CB1 Receptor Signaling

Timing-dependent long-term depression (tLTD) is a form of spike timing-dependent plasticity (STDP) that has been attributed to presynaptic NMDA and CB1 receptors at synapses between layer 5 (L5) pyramidal cells (PCs) in visual cortex. Here, we asked whether astrocytes, known for gliotransmission and tripartite synapse formation, are also required. Using quadruple whole-cell recordings in acute slices from C57BL/6 mice, we found that L5 PC [->] PC tLTD was abolished by the glial metabolic inhibitor sodium fluoroacetate. Disrupting astrocyte Ca2+ signaling through loss-of-function approaches such as AAV-mediated expression of CalEx and BAPTA loading of astrocyte networks consistently prevented tLTD. Optogenetic activation of astrocyte Gq signaling during tLTD induction abolished tLTD and led to potentiation. Since tLTD relies on endocannabinoid (eCB) signaling and astrocytes express CB1 receptors, we conditionally deleted CB1 receptors from astrocytes and found that this manipulation abolished tLTD. Taken together, our results show that L5 PC [->] PC tLTD requires astrocyte Ca2+ signaling and CB1 receptor activation. These findings suggest that astrocyte-dependent control of STDP may represent a general principle across circuit and synapse types. Significance StatementSpike timing-dependent plasticity (STDP) enables neural circuits to adapt based on the precise timing of activity, with timing-dependent long-term depression (tLTD) promoting competition and stabilization. While tLTD is often considered a two-factor process involving pre- and postsynaptic neurons, we show that astrocytes form a key third element. Using targeted loss-of-function approaches, we demonstrate that tLTD at layer-5 pyramidal cell synapses in visual cortex requires astrocyte Ca2+ signaling and CB1 receptors. Unexpectedly, optogenetic stimulation of astrocyte Gq signaling during induction blocked depression and instead triggered potentiation. These findings call for a revision of existing models of STDP and suggest that astrocyte-dependent plasticity may reflect a general regulatory principle across cortical circuits.

neuroscience↗

bioRxiv2026

Distinct NMDA Receptor Pools Determine Diverse Forms of Cortical Plasticity

NMDA receptors (NMDARs) are well-established as coincidence detectors in Hebbian learning, but this requires postsynaptic localization. Presynaptic NMDARs, however, remain controversial due to limitations of pharmacology and calcium imaging. We therefore dissected the function of distinct NMDAR pools using more direct techniques, including immunogold EM, sparse genetic deletion, and paired recordings from layer-5 (L5) pyramidal cell (PC) synapses in mouse primary visual cortex (V1). We found that pre- but not postsynaptic NMDARs regulate both spontaneous and evoked neurotransmitter release. In spike-timing-dependent plasticity, we uncovered a double dissociation: timing-dependent long-term depression (tLTD) requires pre- but not postsynaptic NMDARs, whereas timing-dependent long-term potentiation (tLTP) needs post- but not presynaptic NMDARs. Postsynaptic NMDAR loss also caused developmentally delayed dendritic spine loss and altered axonal and dendritic architecture. In summary, NMDARs do not act as a unified plasticity signal but rather confer location-specific control over diverse forms of synaptic signaling, plasticity, and circuit structure.

neuroscience↗

bioRxiv2023

Structured connectivity in the output of the cerebellar cortex

Circuits in the brain are built from connections between neurons, where the spatial organization and functional properties of these connections determines circuit function. In the cerebellum, Purkinje cells transmit information to neurons in the cerebellar nuclei, but how Purkinje cell - nuclear neuron connections are organized remains unclear. Here, we explored the connections between Purkinje cells and cerebellar nuclear neurons using whole-cell electrophysiology and optogenetics to produce spatial connectivity maps of cerebellar cortical output. We observed non-random connectivity between Purkinje cells and their target neurons, with inputs to cerebellar nuclear neurons clustering along cerebellar transverse zones. While many nuclear neurons received inputs from a single zone, a number of different connectivity motifs were observed. Neurons receiving inputs from all four zones were more common than predicted by a random model and showed topographic organization in the nucleus. Finally, we observed that small Purkinje cell inputs were sufficient to pause the output of nuclear neurons, suggesting that widespread Purkinje cell synchrony may not be necessary to influence cerebellar output. These findings reveal cerebellar nuclear neurons as an important locus of multimodal cerebellar integration.

neuroscience↗

bioRxiv2022

The Developmental Profile of Visual Cortex Astrocytes

Though once thought of as passive support cells for neurons, it is now clear that astrocytes signal via calcium (Ca2+) to trigger gliotransmission that impacts surrounding neurons and synapses. We therefore investigated how astrocytes in layer-5 (L5) mouse visual cortex mature electrophysiologically and morphologically over postnatal days (P) 3 - 30 and how these relate to changes in spontaneous Ca2+ events. Across this age range, resting membrane potential increased, and input resistance decreased. Astrocytes also revealed different membrane responses to voltage steps: notably, membrane responses became more passive with age. Two-photon (2p) imaging of dye-loaded patched cells and confocal imaging revealed that gap-junction coupling increased starting around P7. Morphological reconstructions revealed increased branch density but also shorter branches after P20, suggesting that astrocyte branches may get pruned as dense tiling is established. Finally, we visualized spontaneous Ca2+ transients with 2p microscopy and found that Ca2+ events decorrelated, became more frequent as well as briefer with age. As astrocytes mature, spontaneous Ca2+ activity thus changes from relatively cell-wide, synchronous waves to local transients. Several astrocyte properties were stably mature from ~P15 onwards, although morphology continued to develop further. Our findings provide a descriptive foundation of astrocyte maturation, useful for the study of astrocytic impact on visual cortex critical period plasticity.

neuroscience↗