Biology subjects

Lassalle, O.

Publications and source records attributed to Lassalle, O..

13 recordsLinked to original sources

bioRxiv2026

Compound and sex specific medial prefrontal cortex rewiring after prenatal THC and CBD exposure

The growing perception of cannabinoids as benign has increased perinatal exposure to both {Delta}9-tetrahydrocannabinol (THC) and cannabidiol (CBD), yet their long-term effects on prefrontal circuitry remain incompletely defined. Here we used whole-cell and field electrophysiology in adult mice (P100-140) of both sexes to compare how in utero exposure to THC or CBD (GD5-18) remodels layer-5 pyramidal neurons in the medial prefrontal cortex (mPFC). We quantified intrinsic excitability, excitatory and inhibitory synaptic transmission, the net E/I ratio, spontaneous excitatory and inhibitory currents kinetics, and canonical forms of synaptic plasticity (endocannabinoid-mediated LTD and NMDA-dependent LTP). Both cannabinoids shifted the adult mPFC toward a more pro-excitatory state: the E/I ratio was altered in a compound- and sex-dependent manner, and endocannabinoid-mediated LTD was abolished across groups. THC recapitulated previously reported deficits, producing male-specific increases in intrinsic excitability and accelerating excitatory current kinetics in females, demonstrating a conserved cross-species vulnerability of prefrontal circuits to gestational THC. CBD produced distinct signatures: female offspring showed marked increases in spontaneous excitatory event frequency and amplitude, indicating large-scale reorganization of excitatory and inhibitory inputs, while male offspring exhibited a selective and profound impairment of LTP. The combination of universal eLTD loss and CBD-specific LTP impairment in males yields a bidirectional loss of plasticity: an emergent synaptic rigidity in which circuits are unable to potentiate or depress effectively. Together, these convergent and divergent effects establish that prenatal exposure to THC and CBD produces lasting, sex-dependent rewiring of mPFC circuitry. Our results caution that the non-intoxicating profile of CBD does not preclude durable developmental impact and underscore the importance of considering both compound identity and sex when assessing the neurodevelopmental risks of perinatal cannabinoid exposure.

neuroscience↗

bioRxiv2023

Adaptive Group Behavior of Fragile X Mice in Unfamiliar Environments

Fragile X Syndrome (FXS) stands out as a prominent cause of inherited intellectual disability and a prevalent disorder closely linked to autism. FXS is characterized by substantial alterations in social behavior, encompassing social withdrawal, avoidance of eye contact, heightened social anxiety, increased arousal levels, language deficits, and challenges in regulating emotions. Conventional behavioral assessments primarily focus on short-term interactions within controlled settings. In this study, we conducted a comprehensive examination of the adaptive group behavior of FXS mice over a three-day period, without introducing experimental interventions or task-based evaluations. The data unveiled intricate behavioral anomalies, with the most significant changes manifesting during the initial adaptation to unfamiliar environments. Notably, certain behaviors exhibited a gradual return to typical patterns over time. This dynamic FXS phenotype exhibited heightened activity, featuring increased exploration, amplified social interest, and an unconventional approach to social interactions characterized by a higher frequency of shorter engagements. These findings contribute to the growing understanding of social behavior in individuals with FXS and underscore the significance of comprehending their adaptive responses in various environmental contexts.

animal behavior and cognition↗

bioRxiv2023

Cell-Specific Disruptions in the Basolateral Amygdala-Accumbens Pathway of Fragile X Mice

Fragile X syndrome (FXS), a neurodevelopmental disorder caused by the inactivation of the FMR1 gene, is one of the most common causes of autism spectrum disorder (ASD). People with FXS and ASD often have difficulty regulating their emotions and behaving in a socially appropriate way. The specific neuronal circuits and synaptic dysfunctions involved in social deficits in FXS are not yet fully understood. The basolateral amygdala (BLA) to accumbens core (NAcC) pathway is central to normal social behavior, and we investigated the functionality of this pathway in a novel mouse model of FXS (Fmr1-/y::Drd1a-tdTomato). We used optogenetics to distinguish synapses between BLA neurons and spiny projection neurons (SPNs) in the NAcC. We found that the BLA-NAcC connection in FXS mice displayed heightened synaptic strength along with specific alterations in synaptic plasticity. In FXS, enhanced AMPA and NMDA postsynaptic currents elevated BLA-D2 SPN synaptic strength, while BLA-D1 SPNs increased firing probability occurred without altered transmission. This results in an overall increase in postsynaptic integration in both D1 and D2 SPN BLA-NAcC pathways compared to WT littermates. Further, the absence of FMRP leads to a specific deficit in long-term depression for BLA-D1 SPNs connections. The neurobiological changes identified in this study may underlie the susceptibility to stressors, socio-communicative difficulties, and altered reward-related processes that are characteristic of FXS pathology.

neuroscience↗

bioRxiv2023

Cocaine-induced loss of LTD and social impairments are restored by fatty acid amide hydrolase inhibition

BackgroundA single usage of a drug of abuse can have lasting effects on both the brain and behavior, continuing even after the drug has been metabolized and eliminated from the body. A single dose of cocaine can abolish endocannabinoid-mediated long-term depression (eCB-LTD) in the nucleus accumbens (NAc) within 24 hours of administration. However, it is uncertain whether this altered neuroplasticity entails a behavioral deficit. MethodsOur study employed adult male mice to investigate the effects of a single dose of cocaine (20 mg/kg) on eCB-LTD, saccharin preference, and social interactions 24 hours after administration. We also examined the gene expression in components of the eCB system. The pharmacological increase of anandamide was evaluated using the fatty acid amide hydrolase (FAAH) inhibitor URB597 (1 mg/kg). ResultsAfter a single dose of cocaine, mice displayed altered plasticity, social interactions, and preference for saccharin and a reduction in mRNA levels of the anandamide-catabolizing enzyme NAPE-PLD. We discovered that the FAAH inhibitor URB597 (1 mg/kg) successfully reversed the cocaine-induced loss of eCB-LTD in the NAc and restored normal social interaction in cocaine-exposed mice, but it did not affect their saccharin preference. ConclusionsOverall, this research underlines the neuroplastic changes and subsequent behavioral alterations that occur after the initial use of cocaine, while also suggesting a potential role for anandamide in the early impairments caused by cocaine. The findings highlight the importance of understanding the mechanisms underlying the initiation of drug use and offer a potential therapeutic target.

neuroscience↗

bioRxiv2023

Glutamatergic synaptic deficits in the prefrontal cortex of the Ts65Dn mouse model for Down syndrome

Down syndrome (DS), the most common form of intellectual disability, is a chromosomal disorder caused by having all or part of an extra chromosome 21, leading to intellectual disability. Contrary to the extensive research on the Ts65Dn mouse model of DS in the hippocampus, the synaptic foundation of prefrontal cortex (PFC) malfunction in individuals with DS, including working memory deficits, remains largely unclear. A previous study on mBACtgDyrk1a mice, which overexpress the Dyrk1a gene, showed that this overexpression negatively impacts spine density and synaptic molecular composition, causing synaptic plasticity deficits in the PFC. By comparing Ts65Dn mice, which overexpress multiple genes including Dyrk1a, and mBACtgDyrk1a mice, we aimed to better understand the role of different genes in DS. Results from electrophysiological experiments (i.e., patch-clamp and extracellular field potential recordings ex vivo) in Ts65Dn PFC male mice revealed modifications of intrinsic properties in layer V/VI pyramidal neurons and the synaptic plasticity range. Thus, long-term depression was abolished in Ts65Dn, while synaptic or pharmacological long-term potentiation were fully expressed in Ts65Dn mice. These results, illustrating the phenotypic divergence between the polygenic Ts65Dn model and the monogenic mBACtgDyrk1a model of DS, highlight the complexity of the pathophysiological mechanisms responsible for the neurocognitive symptoms of DS.

neuroscience↗

bioRxiv2022

Dichotomous Intrinsic Properties of Adult Accumbens Medium Spiny Neurons Vanish in the Fragile X Mouse Model of Autism

Fragile X syndrome (FXS), the most common cause of autism and inherited intellectual disability, is caused by the mutation of a single gene, fmr1, which encodes the Fragile X mental retardation protein (FMRP). FXS patients suffer from cognitive, emotional, and social deficits indicative of dysfunction in the nucleus accumbens (NAc), a structure central to the control of social behavior. The major cell type of the NAc, medium spiny neurons (MSNs), are differentiated in two subtypes based on their expression of either dopamine D1 or D2 receptors, their connectivity, and associated behavioral functions. Understanding how the absence of FMRP differentially affects the cellular properties of MSNs is a necessary step to categorize FXS cellular endophenotypes. To address this question, we comprehensively compared the intrinsic passive and active properties of MSN subtypes identified in a novel Fmr1-/y :: Drd1a-tdTomato mouse model allowing in-situ identification of MSN subtypes in FXS mice. Although fmr1 transcripts and their gene product, FMRP, were found in both MSNs subtypes, the results suggest cell-autonomous functions for Fmr1. The opposite membrane properties and action potential kinetics that normally discriminate D1- from D2- MSNs in WT mouse is either reversed or abolished in Fmr1-/y :: Drd1a-tdTomato mice. Multivariate analysis shed light on the compound effects of Fmr1 ablation by revealing how the phenotypic traits that distinguish each cell type in WT are modified in FXS. Together these data show that in Fragile X mice the normal dichotomy that characterizes NAc D1- and D2-MSNs is thrown out of balance, leading to a uniform phenotype that could underlie selected aspects of the pathology.

neuroscience↗

bioRxiv2021

Cannabinoid during adolescence phenocopies reelin haploinsufficiency in prefrontal cortex synapses

In humans and rodents, the protracted development of the prefrontal cortex (PFC) throughout adolescence represents a time for marked vulnerability towards environmental adversities, such as stress or drug exposure. We previously showed that the extracellular matrix protein reelin is an instrumental synaptic modulator that shapes medial PFCs (mPFC) circuitry during maturation and is a critical mediator of the vulnerability to environmental stress. Emerging evidence highlight the role of the endocannabinoid system in the postnatal maturation of the PFC and reelin deficiency influences behavioral abnormalities caused by heavy consumption of THC during adolescence. Could the reelin-dependent maturation of prefrontal networks may be vulnerable to cannabinoid exposure during adolescence? To explore this hypothesis, we studied the effects of a single in-vivo exposure to a synthetic cannabinoid on reelin expression and mPFC functions in adolescent male mice. The results show that a single cannabinoid exposure mimics reelin haploinsufficiency by decreasing prefrontal reelin expression in a layer-specific pattern without changing its transcriptional levels. Furthermore, this treatment impeded synaptic plasticity: adolescent cannabinoid lowered long-term potentiation to the magnitude observed in age-matched reelin haploinsufficient males. Quantitative PCR analysis showed that changes in the mRNA levels of NMDARs does not account for the reduction of TBS-LTP. Together, the data show that exposure to cannabinoid during adolescence phenocopies reelin haploinsufficiency and further identifies reelin as a key component of the vulnerability of PFC to environmental insults.

neuroscience↗

bioRxiv2021

SEX-SPECIFIC TRAJECTORIES OF REELIN-DEPENDENT MATURATION OF DEEP LAYER PREFRONTAL NEURONS

Throughout early adulthood, the anatomical and functional maturation of PFC circuitry continues under the influence of multiple extrinsic and intrinsic factors, most notably electrical activity, and molecular cues. We previously showed that the extracellular matrix protein reelin orchestrates the structural and functional maturation of deep layers medial PFC (mPFC) pyramidal neurons. Additionally, we reported that reelin haploinsufficiency is associated to prefrontal disruptions of long-term memory retention thereby illustrating the eminent role of reelin in cognitive maturation of the PFC. Prefrontal maturation follows a sex-specific developmental pattern, supporting the existence of sexual differences in the morphology-functional properties PFC. Here, we interrogated the role of reelin in the functional maturation of excitatory networks in the mPFC. The developmental trajectory of reelins expression and deep layer pyramidal neurons synaptic plasticity was tracked in the mPFC of male and female mice, from the juvenile period to adulthood. To assess the role of reelin in both sexes, wild-type and heterozygous reeler mice (HRM) were compared. The results show that the maturational profile of reelin expression in the mPFC is sex-dependent and that the developmental trajectory of long-term potentiation is different between wild-type males and females. These data demonstrate reelins influence on prefrontal synapses is sex and period specific.

neuroscience↗

bioRxiv2020

Sex-specific maturational trajectory of endocannabinoid plasticity in the rat prefrontal cortex

The prefrontal cortex (PFC) develops until early adulthood in rodents and humans, but how synaptic plasticity evolves throughout postnatal development is not known. Here, we used a cross-sectional approach to establish the postnatal maturational trajectories of intrinsic properties and synaptic plasticity in the PFC of rats of both sexes. We found that while layer 5 PFC pyramidal neurons from rats of both sexes displayed similar current-voltage relationships, rheobases and resting potentials across all age groups, excitability was lower in female adults compared to the other developmental stages. NMDAR-dependent long-term potentiation and mGluR2/3-mediated long-term depression (LTD) were equally expressed at the juvenile, pubescent and adult developmental stages in animals of both sexes. However, the developmental course of endocannabinoid (eCB)-mediated LTD was sexually dimorphic. First, eCB-LTD emerged during the juvenile period in females. However, although CB1Rs were functional in both sexes at all developmental stages, eCB-LTDs first emerged during pubescence in male. Second, eCB-LTD engaged distinct receptors in males and females depending on their developmental stages. Female rats employ both CB1R and TRPV1R to produce eCB-LTD at the juvenile stage but solely CB1R at pubescence followed by only TRPV1R at adulthood. In contrast, in pubescent and adult males eCB-LTD always and exclusively depended on CB1R. Pharmacological blockade of 2AGs principal degrading enzyme allowed incompetent male juvenile synapses to express eCB-LTD. The data reveal different maturational trajectories in the PFC of male and female rats and provide new cellular substrates to the sex-specific behavioral and synaptic abnormalities caused by adolescent exposure to cannabinoids.

neuroscience↗

bioRxiv2019

Cell-type and endocannabinoid specific synapse connectivity in the adult nucleus accumbens core

The nucleus accumbens (NAc) is a mesocorticolimbic structure that integrates cognitive, emotional and motor functions. Although its role in psychiatric disorders is widely acknowledged, the understanding of its circuitry is not complete. Here we combined optogenetic and whole-cell recordings to draw a functional portrait of excitatory disambiguated synapses onto D1 and D2 medium spiny neurons (MSNs) in the adult mouse NAc core. Comparing synaptic properties of ventral hippocampus (vHipp), basolateral amygdala (BLA) and prefrontal cortex (PFC) inputs revealed a hierarchy of synaptic inputs and feedforward inhibition that depends on the identity of the postsynaptic target MSN. Thus, the BLA is the dominant excitatory pathway onto D1 MSNs (BLA > PFC = vHipp) while PFC inputs dominate D2 MSNs (PFC > vHipp > BLA). Feedforward inhibition of MSN firing too, was input and cell-type specific: while minimal at vHipp-D1 and vHipp-D2 inputs; it inhibited with similar efficacy BLA-D1 or BLA-D2 inputs, was minimal at PFC-D1 but maximal at PFC-D2 inputs. We also tested the hypothesis that endocannabinoids endow excitatory circuits with pathway- and cell-specific plasticity. Thus, while CB1 receptors (CB1R) uniformly depress excitatory pathways irrespective of MSNs identity, TRPV1 receptors (TRPV1R) bidirectionally control inputs onto the NAc core in a pathway-specific manner. Finally, we show how the interplay of TRPV1R/CB1R shapes plasticity at identified BLA-NAc synapses. Together these data shed new light on synapse and circuit specificity in the adult NAc core and illustrate how endocannabinoids contribute to pathway-specific synaptic plasticity.\n\nSIGNIFICANCE STATEMENTWe examined the impact of connections from the ventral hippocampus (vHipp,) basolateral amygdala (BLA) and prefrontal cortex (PFC) onto identified medium spiny neurons (MSN) in the adult accumbens core. We found BLA inputs were strongest at D1 MSNs while PFC inputs dominate D2 MSNs. We evaluated the role of the endocannabinoid system in pathway- and cell-specific plasticity and found that CB1 receptors (CB1R) and TRPV1 receptors (TRPV1R) bidirectionally control synaptic transmission and plasticity onto accumbens MSNs in a pathway- and cell-specific manner. Finally, we clarify how the interplay of TRPV1R/CB1R shapes plasticity at identified BLA-NAc synapses.

neuroscience↗

bioRxiv2018

Sex differences in the behavioral and synaptic consequences of a single exposure to cannabinoid at puberty and adulthood

Heavy cannabis consumption among adolescents is associated with significant and lasting neurobiological, psychological and health consequences that depend on the age of first use. Chronic exposure to cannabinoid (CB) agonists during adolescence alters social behavior and prefrontal cortex (PFC) activity in adult rats. However, sex differences on social behavior as well as PFC synaptic plasticity after acute CB activation remain poorly explored. Here, we determined the consequences of a single CB activation differently affects PFC in males and females by assessing social behavior and PFC neuronal and synaptic functions in rats during pubertal or adulthood periods, 24h after a single in-vivo cannabinoid exposure (SCE). During puberty, SCE reduced play behavior in females but not males. In contrast, SCE impaired sociability in both sexes at adulthood. General exploration and memory recognition remained normal at both ages and both sexes. At the synaptic level, SCE ablated endocannabinoid-mediated long-term depression (eCB-LTD) in the PFC of females of both ages and heightened excitability of PFC pyramidal neurons at adulthood, while males were spared. In contrast, SCE was associated to impaired long-term potentiation in adult males. Together, the data indicate behavioral and synaptic sex differences in response to a single in-vivo exposure to cannabinoid at puberty and adulthood.

neuroscience↗

bioRxiv2018

Sex specific endophenotypes of in-utero cannabinoid exposure

Cannabinoids can cross the placenta, thus may interfere with fetal endocannabinoid signaling during neurodevelopment, causing long-lasting deficits. Despite increasing cannabis consumption during pregnancy, the protracted consequences of prenatal cannabinoid exposure (PCE) remain incompletely understood. Here we report sex-specific differences in behavioral and neuronal deficits in the adult progeny of rat dams exposed to low doses of cannabinoids during gestation. In males, PCE reduced social interaction, ablated endocannabinoid long-term depression (LTD) and heightened excitability of prefrontal cortex pyramidal neurons, while females were spared. Group 1 mGluR and endocannabinoid signaling regulate emotional behavior and synaptic plasticity. Notably, sex-differences following PCE included levels of mGluR1/5 and TRPV1R mRNA. Finally, positive allosteric modulation of mGlu5 and enhancement of anandamide levels restored LTD and social interaction in PCE adult males. Together, these results highlight marked sexual differences in the effects of PCE and introduce strategies for reversing detrimental effects of PCE.

neuroscience↗

bioRxiv2018

Muscarinic M1 receptor modulation of synaptic plasticity in nucleus accumbens of wild-type and fragile X mice

We investigated how metabotropic Acetylcholine receptors control excitatory synaptic plasticity in the mouse nucleus accumbens core. Pharmacological and genetic approaches revealed that M1 mAChRs trigger multiple and interacting forms of synaptic plasticity. As previously described in the dorsal striatum, moderate pharmacological activation of M1 mAChR potentiated postsynaptic NMDARs. The M1-potentiation of NMDAR masked a previously unknown coincident TRPV1-mediated long-term depression (LTD). In addition, strong pharmacological activation of M1 mAChR induced canonical retrograde LTD, mediated by presynaptic CB1R. In the fmr1-/y mouse model of Fragile X, we found that CB1R but not TRPV1 M1-LTD was impaired. Finally, pharmacological blockade of the degradation of anandamide and 2-arachidonylglycerol, the two principal eCBs restored fmr1-/y LTD to wild type levels. These findings shed new lights on the complex influence of Acetylcholine on excitatory synapses in the nucleus accumbens core and identify new substrates of the synaptic deficits of Fragile X.

neuroscience↗