Molecular genetic investigations on the physiological role of the Cannabinoid receptor CB 1 in the central nervous system of the mouse
Final Report Abstract
The major discovery of this granting period is the observation that CB1 receptors contain differential functions, depending on the presence on glutamatergic and GABAergic terminals. Since our first presentation of the expression of CB1 on these different neuronal populations in 1999 (Marsicano and Lutz, EJN 1999), the field has hotly debated on this issue. For a long time, several other investigators fundamentally questioned our proposal. However, by using a multidisciplinary approach (sophisticated mouse genetics, electrophysiology, immunostainings and behavioural assays), we were able to convincingly show both the presence and the function of CB1 on glutamatergic terminals. The present hypothesis is that endocannabinoid system as a whole functions as a system to maintain the body's homeostasis. If considering CB1 function on glutamatergic and GABAergic neurons, respectively, we observed in several assays that antagonizing actions are mediated by CB1 depending on the expression site. Further studies will have to further substantiate this notion. Several surprising observations occurred: The involvement of CB1 in habituation-like processes was not expected. This asigns a much broader function of CB1 in alleviating fear memories and may give novel perspectives in using the endocannabinoid system as a target in the treatment of PTSD. The finding of the central importance of CB1 in glutamatergic neurons is surprising in the light that CB1 is expressed in this neuronal population to a much less degree that in GABAergic neurons. Consequently, future experiments in the lab will address biochemical differences of CB1 in these two different neuronal subpopulations. Recent collaborations using our conditional knock-outs have revealed CB1 functions also during neural development, including proliferation of neural progenitor cells, migration of neurons, and in axonal projection to target structures. Consequently, we will use new cre mouse lines, enabling us to inactivate CB1 functions in the adult in a cell-type and time-specific manner. The work by Marsicano et al. (2003) obtained attention, e.g. by BBC and Deutsche Ärztezeitung and other newspapers. It obtained the rating "9, exceptional" at the Faculty of 1000 Biology. The work by Azad et al. (2004) enabled Dr. Azad to obtain a prize from the Deutsche Gesellschaft zum Studium des Schmerzes e.V. (DGSS). The work by Kamprath et al. (2006) obtained the rating "3, recommended" at the Faculty of 1000 Biology. The work by Monory et al. (2006) was well received. It was discussed in Die Welt on 22.09.06 and in a release by Neuron Cell press on 17.08.2006. Later, it was discussed in an article on epilepsy by Süddeutsche Zeitung. The work was presented as a symposia talk at the FENS in Vienna (2006). It was among the top 10 downloads at Neuron home page for several weeks.
Publications
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(2003) CB1 cannabinoid receptors mediate on-demand defense against excitotoxicity. Science 302:84-88
Marsicano G, Goodenough S, Monory K, Hermann H, Eder M, Cannich A, Azad SC, Grazia Cascio M, Ortega Gutierrez S, van der Stelt M, Luz Lopez- Rodriguez M, Casanova E, Schütz G, Zieglgänsberger W, Di Marzo V, Behl C, Lutz B
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(2004) Circuitry for associative plasticity in the amygdala involves endocannabinoid signaling. J Neurosci 24:9953-9961
Azad SC, Memory K, Marsicano G, Cravatt BF, Lutz B, Zieglgänsberger W, Rammes G
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(2004) On-demand activation of the endocannabinoid system in the control of neuronal excitability and epileptiform seizures. Biochem Pharm 68:1691-1998
Lutz B
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(2004). CB1 cannabinoid receptors modulate kinase and phosphatase activity during extinction of conditioned fear in mice. Learning & Memory 11:625-632
Cannich A, Wotjak C, Kamprath C, Lutz B, Marsicano G
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(2006) Cannabinoid CB1 receptor mediates fear extinction via habituation-like processes. J Neurosci 26:6677-86
Kamprath C, Marsicano G, Tang J, Monory K, Bisogno T, Di Marzo V, Lutz B, Wotjak CT
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(2006) Evidence for the control of excitatory synaptic transmission by activation of cannabinoid receptor type 1 (CB1) located on presynaptic terminals of principal neurons in the cortex. J Neurosci 26:5794-9
Domenici MR, Azad SC, Schierloh A, Wotjak CT, Dodt HU, Marsicano G, Zieglgänsberger W, Lutz B, Rammes G
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(2006) Neuromodulatory functions of the endocannabinoid system, J Endocrinol Invest 29 (3 suppl):27-46
Marsicano G, Lutz B
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(2006) The endocannabinoid system controls key epileptogenic circuits in the hippocampus. Neuron 51:455- 66
Monory K, Massa F, Egertova M, Eder M, Blaudzun H, Westenbroek R, Kelsch W, Jacob W, Marsch R, Ekker M, Long J, Rubenstein JL, Goebbels S, Nave KA, During M, Klugmann M, Wolfel B, Dodt HU, Zieglgänsberger W, Wotjak CT, Mackie K, Elphick MR, Marsicano G, Lutz B
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(2006) The role of the amygdala in the extinction of conditioned fear. Biol Psychiatry 60:322-328
Barad M, Gean PW, Lutz B
