All for One But Not One for All: Excitatory Synaptic Scaling and Intrinsic Excitability Are Coregulated by CaMKIV, Whereas Inhibitory Synaptic Scaling Is Under Independent Control
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Neocortical circuits use a family of homeostatic plasticity mechanisms to stabilize firing, including excitatory and inhibitory synaptic scaling and homeostatic intrinsic plasticity (Turrigiano and Nelson, 2004). All three mechanisms can be induced in tandem in cultured rat neocortical pyramidal neurons by chronic manipulations of firing, but it is unknown whether they are coinduced by the same activity-sensors and signaling pathways, or whether they are under independent control. Calcium/calmodulin-dependent protein kinase type IV (CaMKIV) is a key sensory/effector in excitatory synaptic scaling that senses perturbations in firing through changes in calcium influx, and translates this into compensatory changes in excitatory quantal amplitude (Ibata et al., 2008; Goold and Nicoll, 2010). Whether CaMKIV also controls inhibitory synaptic scaling and intrinsic homeostatic plasticity was unknown. To test this we manipulated CaMKIV signaling in individual neurons using dominant-negative (dn) or constitutively-active (ca) forms of nuclear-localized CaMKIV and measured the induction of all three forms of homeostatic plasticity. We found that excitatory synaptic scaling and intrinsic plasticity were bidirectionally coinduced by these manipulations. In contrast, these cell-autonomous manipulations had no impact on inhibitory quantal amplitude. Finally, we found that spontaneous firing rates were shifted up or down by dnCaMKIV or caCaMKIV, respectively, suggesting that uncoupling CaMKIV activation from activity generates an error signal in the negative feedback mechanism that controls firing rates. Together, our data show that excitatory synaptic scaling and intrinsic excitability are tightly coordinated through bidirectional changes in the same signaling pathway, whereas inhibitory synaptic scaling is sensed and regulated through an independent control mechanism. SIGNIFICANCE STATEMENT Maintaining stable function in highly interconnected neural circuits is essential for preventing circuit disorders, and is accomplished through a set of negative feedback mechanisms that sense and compensate for perturbations in activity. These “homeostatic” mechanisms can target synaptic excitation, synaptic inhibition, and intrinsic excitability, but whether they are independently controlled is not known. We find that synaptic excitation and intrinsic excitability are coregulated in individual neurons through CaMKIV signaling, which is tightly controlled by neuronal activity. In contrast, synaptic inhibition is unaffected by changes in firing or CaMKIV signaling in individual neurons. These results show that circuit stability is controlled both through cell-autonomous mechanisms that regulate some aspects of excitability, as well as circuit-level mechanisms that adjust inhibition.
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GIRK channels hyperpolarize the membrane and raise rheobase, offering a tractable target for post-induction stabilization.
“GIRK channels hyperpolarize the membrane and raise rheobase, offering a tractable target for post-induction stabilization [361].”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [361]
The section on intrinsic excitability reports rheobase changes after CaMKIV manipulation, not GIRK-channel activation; its observed trend toward increased rheobase was not significant. Searches for GIRK-mediated hyperpolarization and post-induction stabilization found no passage addressing either point (page numbers unavailable in our copy). (LLM, conf=0.76)
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- Authors
- Joseph, A., & Turrigiano, G. G.
- Affiliations
- Brandeis University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2017-06-07
- Volume
- 37
- Issue
- 28
- Pages
- 6778-6785
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC5508258
- OpenAlex
- W2622710127
- Cited by
- 94
- References
- 61
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 13 · 2023: 9 · 2022: 9 · 2021: 13 · 2020: 12 · 2019: 12 · 2018: 11 · 2017: 2
- FWCI
- 4.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R37NS092635, P01NS079419)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- intrinsic excitability, CaMKIV, neocortical pyramidal neurons, spontaneous firing rate, negative feedback, activity-dependent plasticity, circuit stability, calcium signaling, calmodulin
- MeSH terms
- Action Potentials, Animals, Animals, Newborn, Cells, Cultured, Female, Male, Neural Inhibition, Synaptic Transmission, Neuronal Plasticity, Pyramidal Cells, Excitatory Postsynaptic Potentials, Rats, Long-Evans, Rats, Calcium-Calmodulin-Dependent Protein Kinase Type 4
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