Multivariate synaptic and behavioral profiling reveals new developmental endophenotypes in the prefrontal cortex
The postnatal maturation of the prefrontal cortex (PFC) represents a period of increased vulnerability to risk factors and emergence of neuropsychiatric disorders. To disambiguate the pathophysiological mechanisms contributing to these disorders, we revisited the endophenotype approach from a developmental viewpoint. The extracellular matrix protein reelin which contributes to cellular and network plasticity, is a risk factor for several psychiatric diseases. We mapped the aggregate effect of the RELN risk allele on postnatal development of PFC functions by cross-sectional synaptic and behavioral analysis of reelin-haploinsufficient mice. Multivariate analysis of bootstrapped datasets revealed subgroups of phenotypic traits specific to each maturational epoch. The preeminence of synaptic AMPA/NMDA receptor content to pre-weaning and juvenile endophenotypes shifts to long-term potentiation and memory renewal during adolescence followed by NMDA-GluN2B synaptic content in adulthood. Strikingly, multivariate analysis shows that pharmacological rehabilitation of reelin haploinsufficient dysfunctions is mediated through induction of new endophenotypes rather than reversion to wild-type traits. By delineating previously unknown developmental endophenotypic sequences, we conceived a promising general strategy to disambiguate the molecular underpinnings of complex psychiatric disorders and for the rational design of pharmacotherapies in these disorders.
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International Associated Laboratory INSERM - Indiana University
The International Associated Laboratory INSERM-Indiana University was created by INSERM. CannaLab associates our lab and the laboratory of Pr. Ken Mackie, Director of the Gill Center For Biomolecular Medicine (Indiana University, Bloomington USA). Our project aims at shedding new light on the structural, molecular and functional synaptic substrates of the sex-specific effects of adolescent cannabis use on behavior.
Molecular Psychiatry: Reelin a new mechanism for how eating high-fat foods in excess during adolescence alters executive functions
Chances are that children who eat excessive amounts of fatty foods will not only become obese, but will develop cognitive and psychiatric problems when they are older, a study in mice suggests. This is because, according to a recent study, diets rich in fat deplete the levels of a key protein known to help synapses in the brain to work properly. In turn, this leads to a dip in several forms of cognitive functions, such as behavioral flexibility and memory.
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Hypervulnerability of the adolescent prefrontal cortex to nutritional stress via reelin deficiency. M A Labouesse, O Lassalle, J Richetto, J Iafrati, U Weber-Stadlbauer, T Notter, T Gschwind, L Pujadas, E Soriano, A C Reichelt, C Labouesse, W Langhans, P Chavis# & U Meyer#; shared seniority ; Molecular Psychiatry volume 22, pages 961–971 (2017)
Poor adolescent diet may influence brain and behavior in adulthood
Adolescent male mice fed a diet lacking omega-3 fatty acids show increased anxiety-like behavior and worse performance on a memory task in adulthood, according to our new research published in The Journal of Neuroscience. Our study suggests adequate nutrition in adolescence is important for the refinement of the adult brain and behavior. The structure and function of the brain continue to change throughout adolescence, at the same time that teenagers gain increasing independence and begin to make their own food choices. Since high-calorie, low-quality diets tend to be more affordable than healthy ones, teenagers may opt for foods that lack key nutrients important for brain health such as omega-3 polyunsaturated fatty acids (n-3 PUFAs), which cannot be produced by the human body and must be obtained from foods such as fish and vegetables. We fed mice a balanced diet until early adolescence, when some mice were switched to a diet lacking n-3 PUFAs. Mice fed the poor diet during adolescence had reduced levels of n-3 PUFA in the medial prefrontal cortex and the nucleus accumbens in adulthood compared to control mice. The low-quality diet impaired the brain’s ability to fine-tune connections between neurons in these regions.
Synaptic functions of endocannabinoid signaling in health and disease
Endocannabinoids (eCBs) are a family of lipid molecules that act as key regulators of synaptic transmission and plasticity. They are synthetized “on demand” following physiological and/or pathological stimuli. Once released from postsynaptic neurons, eCBs typically act as retrograde messengers to activate presynaptic type 1 cannabinoid receptors (CB1) and induce short- or long-term depression of neurotransmitter release. Besides this canonical mechanism of action, recent findings have revealed a number of less conventional mechanisms by which eCBs regulate neural activity and synaptic function, suggesting that eCB-mediated plasticity is mechanistically more diverse than anticipated. These mechanisms include non-retrograde signaling, signaling via astrocytes, participation in long-term potentiation, and the involvement of mitochondrial CB1. Focusing on paradigmatic brain areas, such as hippocampus, striatum, and neocortex, we review typical and novel signaling mechanisms, and discuss the functional implications in normal brain function and brain diseases. In summary, eCB signaling may lead to different forms of synaptic plasticity through activation of a plethora of mechanisms, which provide further complexity to the functional consequences of eCB signaling.
This article is part of the Special Issue entitled “A New Dawn in Cannabinoid Neurobiology”.
Cell Reports: Endocannabinoid plasticity is a synaptic marker of anxiety following social defeat.
Chronic social defeat stress (CSDS) is a clinically relevant model of mood disorders. The relationship between the CSDS model and a physiologically pertinent paradigm of synaptic plasticity is not known. Here, we found that cluster analysis of the emotional behavior states of mice exposed to CSDS allowed their segregation into anxious and non-anxious groups. Endocannabinoid-mediated spike-timing dependent plasticity (STDP) in the nucleus accumbens was attenuated in non-anxious mice and abolished in anxious mice. Anxiety-like behavior in stressed animals was specifically correlated with their ability to produce STDP. Pharmacological enhancement of 2-arachidonoyl glycerol (2-AG) signaling in the nucleus accumbens normalized the anxious phenotype and STDP in anxious mice. These data reveal that endocannabinoid modulation of synaptic efficacy in response to a naturalistic activity pattern is both a molecular correlate of behavioral adaptability and a crucial factor in the adaptive response to chronic stress.
Clementine Bosch-Bouju#, Thomas Larrieu#, Louisa Linders, Olivier J. Manzoni* and Sophie Laye*
Team FRM 2015-2018
Multi scale study of in utero cannabis exposure
Human studies converge to indicate psychiatric, cognitive, and behavioral effects of cannabis use/abuse in both adults and children and the progeny of women users as well as in animal models. Although cannabis (hashish, marijuana) is the most commonly consumed/abused illegal drug by pregnant women very little is known on the consequences of cannabinoid exposure during fetal neurodevelopment and its long term repercussions on neuronal processes. This project aims at understanding the cellular underpinnings of the pathological consequences of in utero cannabis exposure. We will decipher how exposure to cannabis during fetal life causes protracted changes in synaptic functions, brain circuits, in vivo neuronal ensembles activity and associated behaviors. We propose a multiple scale approach that combines well established methods of electrophysiology and imaging and cutting edge techniques (photometry of genetically encoded calcium indicators) in freely behaving rodents.
Work in the laboratory focuses on the role of hub proteins/supramolecular complexes in the etiology of neuropsychiatric diseases. Our research strategy is to analyze the mechanisms and the functions of synaptic signalosome in neuronal integration in pathophysiological conditions using animal model of neuropsychiatric diseases (depression, mental retardation, autism, drug addiction).
Major neuropsychiatric disorders including mental retardation, autism, schizophrenia, depression and addiction are accompanied by alterations of the very substrates of the neural code.
At the synaptic level, the neural code is processed by postsynaptic molecular machines made of macromolecular complexes complexes of interacting proteins organized into a scale-free network.
The “small world” nature of multiprotein complexes implies highly organized interconnected structures where changes in one protein can readily alter the functions of many others. Therefore, proteins with the higher number of connections, the so-called “hub proteins” are of particular significance to network integrity and synaptic plasticity.
Synaptic plasticity underlies dynamic changes in neural networks that are triggered by environmental stimuli and individual experiences. Such dynamic changes are fundamental to normal brain functions. From early development to adulthood, synaptic plasticity is necessary to learn new abilities, form new memories and generate new adaptive behaviors.
Aberrant synaptic transmission and/or plasticity participate to the etiology of neuropsychiatric diseases: disruption of a molecular cog of the synaptic machine causes or result in deficits in synaptic plasticity and leads to abnormal information processing.
The concept that major brain diseases are either caused by or result in deficits in synaptic plasticity is supported by the observation that most synaptic hub proteins (e.g. NMDAR, mGluR1/5) are involved in psychiatric and/or neurodegenerative disease.
Most neuropsychiatric disorders are accompanied by significant social, emotional and cognitive problems. Surprisingly, the neuronal substrates of emotional perturbation are seldom studied in the context of these pathologies.
Synapse; synaptic plasticity, Extracellular matrix; Accumbens, Prefrontal cortex; Reelin; Endocannabinoid, mGluR, NMDAR; Pharmacotherapy; Autism, Fragile X, Nutrition, Adolescence.
Electrophysiology: Extracellular; Multi Electrode Arrays; Patch Clamp in vitro & ex vivo
Two photon imaging; Calcium Imaging in vivo in freely moving, behaving rodents.
- Barbara Bardoni (Autism / CNRS UMR 7275, IPMC, Nice).
- Sophie Layé (Nutrition & Integrative Neurobiology / INRA UMR 1286, Bordeaux).
- Urs Meyer (University of Zürich, Switzerland)
- Ken Mackie (Indiana University, Bloomington USA).
-Rainer Spanagel (CB1R and mGluRs in the mesolimbic pathway / Mainz University, Germany)
- NIH (co-P.I. O. MANZONI & K. MACKIE)
- FRC (De CHEVIGNY, P. CHAVIS)
- FRM (P.I. O. MANZONI)
- Cannado / ANR Samenta (P.I. A.L. PELISSIER) -
- CYFIP-Aut / ANR Blanc (P.I. B. BARDONI)
Google Scholar P. Chavis