I think there are two reasons. First, the paper has overthrown the hitherto dominant "CB3" hypothesis, by clearly showing that CB1 is present and functional at hippocampal excitatory synapses. Second, the information about the type of cannabinoid receptor (CB1 or CB3) existing in the brain is important for both basic and clinical research in the cannabinoid research field.

  Does it describe a new discovery, methodology, or synthesis of knowledge?

“I think that basic studies on the endocannabinoid system are important from the clinical point of view, because several molecules involved in the endocannabinoid signaling have been anticipated as novel targets of drugs for pain, obesity, neurodegenerative diseases, and addiction.”

For hippocampal excitatory synapses, contributions of CB1, CB3, and some other unidentified cannabinoid receptors have been suggested. A main drawback of the CB1 hypothesis was that anatomical studies failed to detect CB1 immunoreactive signals at these terminals.

In this work, we have succeeded in labeling presynaptic CB1 at these synapses by using the anti-CB1 antibody raised by Masahiko Watanabe, the coauthor of this paper. Together with electrophysiological experiments using CB1-knockout mice, we provide conclusive evidence for the presence of functional CB1 at these excitatory synapses.

  Would you summarize the significance of your paper in layman’s terms?

Cannabinoid receptors are the targets of marijuana. So far, two types of receptors have been cloned, and termed CB1 and CB2. CB1 is widely distributed in the nervous system, whereas CB2 is mainly expressed in the immune system of the periphery. The possible existence of additional cannabinoid receptors in the brain has been proposed. One example is the so-called"CB3" receptor that has been suggested to exist at hippocampal excitatory synapses.

Our paper, however, contradicts the CB3 hypothesis, and clearly demonstrates that CB1 is the major cannabinoid receptor at these and other excitatory synapses. The paper also provides information as to the density of CB1 along presynaptic fibers.

  How did you become involved in this research and were any particular problems encountered along the way?

We were attracted by the phenomena that postsynaptic neurons release some "retrograde messenger" which suppresses transmitter release from presynaptic terminals. Several years ago, we and two other research groups had finally found that endocannabinoids mediate the retrograde signal. Since then, we have been working to find out how the endocannabinoid system functions in the brain.

  Where do you see your research leading in the future?

At the cellular level, it is now clear how endocannabinoids are produced, are released, function at presynaptic terminals, and are degraded. At the whole-animal level, it is also clear that the endocannabinoid system is involved in many aspects of brain function. We would like to elucidate the link between these two.

  Are there any social or political implications for your research?

I think that basic studies on the endocannabinoid system are important from the clinical point of view, because several molecules involved in the endocannabinoid signaling have been anticipated as novel targets of drugs for pain, obesity, neurodegenerative diseases, and addiction.