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Contributed by Tomas G. M. Hökfelt, December 17, 2020 (sent for review December 2, 2019; reviewed by Alon Amir, Marco Capogna, and Joseph E. LeDoux)
Significance
Unconscious reactions to threat orchestrated by subcortical brain structures are critical to save the individual at peril. The innate behavioral responses can be modulated by associative learning processes in which the amygdaloid complex gates active motor commands to avoid danger. At the cellular level, glutamatergic neurotransmission through postsynaptic NMDA receptors drives threat-induced changes in synaptic function. Here, we show that the availability of NMDA receptors in the postsynapse is modulated by secretagogin, a Ca2+ sensor protein. Chemogenetic inactivation of secretagogin-expressing neurons, or ablation of secretagogin itself, provides causality for the role of Ca2+-dependent feedback regulation at the cellular level.
Abstract
The perception of and response to danger is critical for an individual’s survival and is encoded by subcortical neurocircuits. The amygdaloid complex is the primary neuronal site that initiates bodily reactions upon external threat with local-circuit interneurons scaling output to effector pathways. Here, we categorize central amygdala neurons that express secretagogin (Scgn), a Ca2+-sensor protein, as a subset of protein kinase Cδ (PKCδ)+ interneurons, likely “off cells.” Chemogenetic inactivation of Scgn+/PKCδ+ cells augmented conditioned response to perceived danger in vivo. While Ca2+-sensor proteins are typically implicated in shaping neurotransmitter release presynaptically, Scgn instead localized to postsynaptic compartments. Characterizing its role in the postsynapse, we found that Scgn regulates the cell-surface availability of NMDA receptor 2B subunits (GluN2B) with its genetic deletion leading to reduced cell membrane delivery of GluN2B, at least in vitro. Conclusively, we describe a select cell population, which gates danger avoidance behavior with secretagogin being both a selective marker and regulatory protein in their excitatory postsynaptic machinery.
Footnotes
- ↵1To whom correspondence may be addressed. Email: Tomas.Hokfelt{at}ki.se or alpar.alan{at}med.semmelweis-univ.hu.
Author contributions: D.Z., D.D.P., K.S., M.P., T.H., T.G.M.H., and A.A. designed research; Z.H., D.Z., R.A.R., J.H., A.I., A.Z., D.D.P., D.L., and A.A. performed research; M.P. and T.H. contributed new reagents/analytic tools; Z.H., R.A.R., J.H., A.I., A.Z., D.D.P., D.L., K.S., T.G.M.H., and A.A. analyzed data; and Z.H., T.H., T.G.M.H., and A.A. wrote the paper.
Reviewers: A.A., Rutgers University; M.C., University of Aarhus; and J.E.L., New York University.
The authors declare no competing interest.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1921123118/-/DCSupplemental.
Data Availability.
All study data are included in the article and/or SI Appendix.
Published under the PNAS license.
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Secretagogin marks amygdaloid PKCδ interneurons and modulates NMDA receptor availability
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- Neuroscience
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