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The Journal of Neuroscience, December 10, 2008, 28(50):13532-13541; doi:10.1523/JNEUROSCI.0847-08.2008

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Cellular/Molecular
The Endocannabinoid 2-Arachidonoylglycerol Is Responsible for the Slow Self-Inhibition in Neocortical Interneurons

Silvia Marinelli,¹ Simone Pacioni,¹ Tiziana Bisogno,² Vincenzo Di Marzo,² David A. Prince,³ John R. Huguenard,³ and Alberto Bacci¹

¹European Brain Research Institute, 00143 Rome, Italy, ²Endocannabinoid Research Group, Istituto di Chimica Biomolecolare–Consiglio Nazionale delle Ricerche, 80078 Pozzuoli, Napoli, Italy, and ³Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305

Correspondence should be addressed to Dr. Alberto Bacci, European Brain Research Institute, Via del Fosso di Fiorano 64, 00143 Roma, Italy. Email: a.bacci{at}ebri.it

In the CNS, endocannabinoids are identified mainly as two endogenous lipids: anandamide, the ethanolamide of arachidonic acid, and 2-arachidonoylglycerol (2-AG). Endocannabinoids are known to inhibit transmitter release from presynaptic terminals; however we have recently demonstrated that they are also involved in slow self-inhibition (SSI) of layer V low-threshold spiking (LTS) interneurons in rat somatosensory cortex. SSI is induced by repetitive firing in LTS cells, which can express either cholecystokinin or somatostatin. SSI is triggered by an endocannabinoid-dependent activation of a prolonged somatodendritic K⁺ conductance and associated hyperpolarization in the same cell. The synthesis of both endocannabinoids is dependent on elevated [Ca²⁺]_i such as occurs during sustained neuronal activity. To establish whether 2-AG mediates autocrine LTS-SSI, we blocked its biosynthesis from phospholipase C (PLC) and diacylglycerol lipases (DAGLs). Current-clamp recordings from LTS interneurons in acute neocortical slices showed that inclusion of DAGL inhibitors in the whole-cell pipette prevented the long-lasting hyperpolarization triggered by LTS cell repetitive firing. Similarly, extracellular applications of a PLC inhibitor prevented SSI in LTS interneurons. Moreover, metabotropic glutamate receptor-dependent activation of PLC produced a long-lasting hyperpolarization which was prevented by the CB1 antagonist AM251, as well as by PLC and DAGL inhibitors. The loss of SSI in the presence of intracellular DAGL blockers confirms that endocannabinoid production occurs in the same interneuron undergoing the persistent hyperpolarization. Since DAGLs produce no endocannabinoid other than 2-AG, these results identify this compound as the autocrine mediator responsible for the postsynaptic slow self-inhibition of neocortical LTS interneurons.

Key words: neocortex; endocannabinoids; interneurons; 2-AG; inhibition; SSI

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Received Oct. 22, 2008; accepted Oct. 27, 2008.

Correspondence should be addressed to Dr. Alberto Bacci, European Brain Research Institute, Via del Fosso di Fiorano 64, 00143 Roma, Italy. Email: a.bacci{at}ebri.it

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