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Cell-type-specific identification of mRNAs translated by cannabinoids in the hippocampus: from signaling to behavior

Final Report Summary - CANCELLTRANS (Cell-type-specific identification of mRNAs translated by cannabinoids in the hippocampus: from signaling to behavior)

Marijuana is the most consumed illicit drug for recreational purposes and has been widely reported to alter memory function in humans as well as in animal models. The cognitive deficits induced by delta9-tetrahydrocannabinol (THC) represent a major negative consequence associated with cannabis consumption and a drawback for its therapeutic use. Despite accumulating evidence demonstrating the memory impairment induced by cannabinoids, very little is known regarding the molecular mechanisms engaged as well as the brain areas and cellular populations involved. The overall goal of this research proposal was to elucidate the molecular mechanisms triggered in response to cannabis exposure selectively in CA1 pyramidal neurons of the dorsal hippocampus that might underlie cognitive deficits.

Taken into account the hundreds of intermingled cell types in the brain, this research proposal has benefited from a powerful new technology, the RiboTag approach, which allows analyzing the protein expression profile within any given cell population. This is of particular interest for the design of novel drugs, which will be able to target a widespread expressed protein in a particular cell population, being more precise with great efficacy and reduced side effects.

By generating/characterizing a double transgenic mouse line and combining state-of-the-art technologies including tagged-ribosome immunoprecipitation and RNA-sequencing, this multidisciplinary project allowed us to elucidate 2 key proteins that are synthesized in CA1 cells after THC exposure, which might play a key role in memory impairment. We targeted this cell population since it has been observed to undergo morphological rearrangements and synaptic plasticity alterations after cannabis exposure and, interestingly, is where mTOR signaling pathway activation takes place, which is involved in the THC-induced memory impairment.

We also took advantage of the RiboTag methodology to address the neurobiological substrates involved in the cognitive deficits associated to Fragile X Syndrome (FXS), which is the most common inherited form of intellectual disability. Since a mild increase in protein synthesis has been reported in a mouse model of FXS, we aimed to decipher the protein expression profile of CA1 pyramidal cells, hypothesizing that an altered protein synthesis might contribute to memory impairment in a similar manner as THC acts. Interestingly, by comparing the profiles of a mouse model of FXS and the control group we found 78 differentially expressed genes, some of which are found to play a key role in plasticity and memory.

This work has contributed to bridge de gap still remaining between molecular mechanisms and behavioral responses in the neuroscience field. On the one hand, we elucidated novel neurobiological substrates concerning the consequences of THC exposure, which represents a major problem since marijuana is the most commonly used illicit drug in Europe (73.6 million or 21.7% of people aged 15-64 used cannabis in their lifetime) according to the European Monitoring Centre for Drugs and Drug Addiction report (2014). On the other hand, we provide new molecular insights into the pathophysiology of FXS, the most common form of inherited intellectual disability. Advances in the molecular basis of memory impairment are expected to contribute to understanding pathological memory deficits and improving the design of novel target-specific drugs, which will have a dramatic impact on the quality citizens’ life, which is one of the priorities of H2020 within the European health program.

One manuscript involving the effects of cannabinoids and another concerning the neurobiological substrates of Fragile X Syndrome are in preparation. Moreover, the expertise acquired in the Ribotag approach allowed me to participate in other projects as well as to acquire a strong knowledge on mRNA translation, which gave me the opportunity to be involved in other studies assessing the role of the ribosomal protein S6 in translation.

During the IEF fellowship, my training included learning a wide variety of molecular biology techniques, intra-structure viral administration, communication abilities, as well as project management and organization. I also visited other laboratories to learn new methodology and I fruitfully established one European and three national collaborations regarding the Ribotag methodology. My scientific maturation was promoted by weekly lectures and seminars given by well-known international experts in the neuroscience field in the host institute as well as numerous conferences and courses. I also gained professional maturity by mentoring three undergraduate students and co-supervised two PhD students and one technician in an international environment. Moreover, I participated in a thesis defense committee as a jury member. Altogether, these two years of IEF fellowship gave me the opportunity to make great scientific contributions, broaden my knowledge in neurobiology, widen my competences as a researcher, improve my independence thinking and further establish my own line of molecular biology research in the memory field. Therefore, I am planning to apply for the ERC Starting Grant next year.