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Endocannabinoid signaling as a synaptic circuit breaker in neurological disease


Cannabis sativa is one of the oldest herbal plants in the history of medicine. It was used in various therapeutic applications from pain to epilepsy, but its psychotropic effect has reduced its usage in recent medical practice. However, renewed interest has been fueled by major discoveries revealing that cannabis-derived compounds act through a signaling pathway in the human body. Here we review recent advances showing that endocannabinoid signaling is a key regulator of synaptic communication throughout the central nervous system. Its underlying molecular architecture is highly conserved in synapses from the spinal cord to the neocortex, and as a negative feed-back signal, it provides protection against excess presynaptic activity. The endocannabinoid signaling machinery operates on demand in a synapse-specific manner; therefore, its modulation offers new therapeutic opportunities for the selective control of deleterious neuronal activity in several neurological disorders.

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Figure 1: Activation of the perisynaptic signaling machinery (PSM) evokes retrograde endocannabinoid signaling.
Figure 2: Operation of the perisynaptic signaling machinery as a synaptic circuit breaker.
Figure 3: Molecular mechanism of endocannabinoid-mediated long-term depression.


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This work was supported by the Howard Hughes Medical Institute, the Egészségügyi Tudományos Tanács 561/2006, the János Bolyai scholarship (I.K.) and the US National Institutes of Health DA009158 and European Union Contract LSHM-CT-2004-005166. We are very grateful to N. Hájos, K. Mackie, D. Piomelli and M. Watanabe for their long-term collaborative support of our work on the endocannabinoid system and to I. Mody and N. Hájos for their comments on the manuscript. We are also indebted to B. Baksa, G. Nyiri and B. Dudok for their help with the preparation of figures.

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Correspondence to István Katona or Tamás F Freund.

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Katona, I., Freund, T. Endocannabinoid signaling as a synaptic circuit breaker in neurological disease. Nat Med 14, 923–930 (2008).

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