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Jacob, Wolfgang (2007): Role of the Cannabinoid Receptor Type 1 (CB1) in Synaptic Plasticity, Memory and Emotionality. Dissertation, LMU München: Fakultät für Biologie



The present work focused on the role of the cannabinoid receptor type 1 (CB1) in synaptic plasticity, memory and emotionality in mice. CB1 is abundantly expressed in the central nervous system and is mainly (if not exclusively) located on GABAergic and glutamatergic nerve cells. CB1 is a G-protein coupled receptor which is essentially inhibiting transmitter release from presynaptic GABAergic or glutamatergic nerve terminals. To differentiate between the physiological significance of CB1 expressed on glutamatergic and GABAergic nerve terminals, the studies included work with three different CB1-deficient mouse lines: A conventional knock-out mouse line (total-CB1- ko mice) with a deficiency of CB1 in the entire brain and two conditional knock-out mouse lines using the Cre/lox P recombination system, and leading to cell type specific deficiency of CB1 on GABAergic neurons (GABA-CB1-ko mice) or glutamatergic neurons (Glu-CB1-ko mice). As a common model for alterations in synaptic plasticity and hippocampus-dependent memory, we studied long-term potentiation in the hippocampus at first. The hippocampus is an essential brain structure being involved in spatial and episodic-like memory. We showed that there is an increase of hippocampal LTP in vivo at the perforant path-dentate gyrus granule cell synapse in total-CB1-ko mice, but failed to detect any difference in LTP levels for GABA-CB1-ko and Glu-CB1-ko mice. Also, short-term plasticity using a paired-pulse stimulation protocol is unchanged in the three mouse lines. Eventually, augmented theta rhythm that is believed to underlie enhanced cognitive abilities could not be found in total-CB1-ko mice. Our hypothesis of memory improvement in CB1-deficient mouse lines could not be verified in three tests for memory that are based on a spontaneous preference for novelty: The social recognition test, the object recognition test and the open field habituation test. We consequently tested the mice in two memory tasks that rely on an aversive test situation. In the water maze spatial discrimination task, again no differences could be assessed for acquisition of the task in total-CB1-ko and Glu-CB1-ko mice. Curiously, Glu-CB1-ko mice demonstrate more flexible behaviour in reversal learning indicating that CB1 on glutamatergic neurons may lead to perseverant and persistent behaviour. Eventually, we could show for the first time that there is a differential contribution of CB1 on either GABAergic neurons or glutamatergic neurons in the background contextual fear conditioning task. Here, mice were tested in the shock context and in a different context containing the grid floor as a similar aspect to the shock context, called grid context. GABA-CB1-ko mice reveal increased fearful behaviour specifically in the grid context. This might indicate an increased context generalisation and/or a feature learning strategy in GABA-CB1-ko mice. In contrast, Glu-CB1-ko mice display increased fearful behaviour specifically for the shock context, indicating a conjunctive learning strategy. Total-CB1-ko mice showed an increased fear response in both contexts, representing a mixed phenotype of Glu-CB1-ko and GABA-CB1-ko mice. Another novel finding confirming a large body of evidence is the fact that total-CB1-ko and Glu-CB1-ko mice manifest a deficit of extinction for the conditioned tone, providing first evidence that CB1 on glutamatergic neurons is essential for short-term extinction of auditory-cued fear memory. Any changes in memory performance might be obscured by altered emotionality in the knockout mouse lines. In classical tests for anxiety such as the elevated plusmaze and the light/dark box, we found a tendency of increased anxiety in total-CB1- ko and Glu-CB1-ko mice and a tendency of a decrease of anxiety in GABA-CB1-komice at most. Strikingly, we were able to show that CB1-ko and Glu-CB1-ko mice, in contrast to GABA-CB1-ko, avoid the open arms of the elevated plus-maze more than wildtype mice on a second exposure to the maze indicating an increased one-trial sensitisation. Furthermore remarkably, CB1-ko and Glu-CB1-ko mice showed increased anxiety-related behaviour whereas GABA-CB1-ko mice revealed an unchanged or anxiolytic phenotype in three different tests of emotionality: The open field test, the novel object exploration test and the novel juvenile exploration test. These tests were carried out under low and high light conditions. Here, as opposed to the elevated plus-maze and the light/dark box, the animals cannot retract from an aversive situation that is bright light in the testing environment which may cause sufficient activation of the endocannabinoid system thus leading to a detectable and profound phenotype in the animals. Interestingly, altered emotionality seems to depend on the averseness of the test situation, as CB1-ko and Glu-CB1-ko animals do not or only mildly differ from their wildtype littermates under lowly aversive conditions but show increased anxiety under highly aversive conditions in the aforementioned tests. This strongly suggests that the endocannabinoid system might dampen states of anxiety in highly aversive and stressful environments. More precisely, CB1 on GABAergic neurons rather leads to an anxiogenic effect, whereas CB1 on glutamatergic neurons prominently leads to an anxiolytic phenotype which we refer to as “the Yin and the Yang effect” of CB1 in emotionality. Altogether, our study illustrates the value of conditional mouse mutants for which celltype specific ablation of a gene of interest exist in order to understand the role of CB1 in synaptic plasticity, memory and emotionality. Our findings add another level of complexity to the picture of endocannabinoid action in fear and anxiety, which has to be considered if the endocannabinoid system is going to be exploited as a therapeutic target for the treatment of anxiety disorders.