TY - JOUR
T1 - Cannabinoid type 2 receptors inhibit GABAA receptor-mediated currents in cerebellar Purkinje cells of juvenile mice
AU - Sadanandan, Sriity Melley
AU - Kreko-Pierce, Tabita
AU - Khatri, Shailesh N.
AU - Pugh, Jason R.
N1 - Funding Information:
Funding:ThisworkwasfundedbyanNIH(www. NIH.gov)grant(R01NS092809)awardedtoJRP. Thefundershadnoroleinstudydesign,data collectionandanalysis,decisiontopublish,or preparationofthemanuscript.
Funding Information:
This work was funded by an NIH (www.NIH.gov) grant (R01 NS092809) awarded to JRP. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2020 Sadanandan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2020/5
Y1 - 2020/5
N2 - Signaling through the endocannabinoid system is critical to proper functioning of the cerebellar circuit. However, most studies have focused on signaling through cannabinoid type 1 (CB1) receptors, while relatively little is known about signaling through type 2 (CB2) receptors. We show that functional CB2 receptors are expressed in Purkinje cells using a combination of immunohistochemistry and patch-clamp electrophysiology in juvenile mice. Pharmacological activation of CB2 receptors significantly reduces inhibitory synaptic responses and currents mediated by photolytic uncaging of RuBi-GABA in Purkinje cells. CB2 receptor activation does not change the paired-pulse ratio of inhibitory responses and its effects are blocked by inclusion of GDP-β-S in the internal solution, indicating a postsynaptic mechanism of action. However, CB2 receptors do not contribute to depolarization induced suppression of inhibition (DSI), indicating they are not activated by endocannabinoids synthesized and released from Purkinje cells using this protocol. This work demonstrates that CB2 receptors inhibit postsynaptic GABAA receptors by a postsynaptic mechanism in Purkinje cells. This represents a novel mechanism by which CB2 receptors may modulate neuronal and circuit function in the central nervous system.
AB - Signaling through the endocannabinoid system is critical to proper functioning of the cerebellar circuit. However, most studies have focused on signaling through cannabinoid type 1 (CB1) receptors, while relatively little is known about signaling through type 2 (CB2) receptors. We show that functional CB2 receptors are expressed in Purkinje cells using a combination of immunohistochemistry and patch-clamp electrophysiology in juvenile mice. Pharmacological activation of CB2 receptors significantly reduces inhibitory synaptic responses and currents mediated by photolytic uncaging of RuBi-GABA in Purkinje cells. CB2 receptor activation does not change the paired-pulse ratio of inhibitory responses and its effects are blocked by inclusion of GDP-β-S in the internal solution, indicating a postsynaptic mechanism of action. However, CB2 receptors do not contribute to depolarization induced suppression of inhibition (DSI), indicating they are not activated by endocannabinoids synthesized and released from Purkinje cells using this protocol. This work demonstrates that CB2 receptors inhibit postsynaptic GABAA receptors by a postsynaptic mechanism in Purkinje cells. This represents a novel mechanism by which CB2 receptors may modulate neuronal and circuit function in the central nervous system.
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U2 - 10.1371/journal.pone.0233020
DO - 10.1371/journal.pone.0233020
M3 - Article
C2 - 32437355
AN - SCOPUS:85085155251
VL - 15
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 5
M1 - e0233020
ER -