6:15pm - 6:35pmGestational ethanol exposure impairs motor skills in female mice through dysregulated striatal dopamine and acetylcholine function
Sebastiano Bariselli
National Institutes of Health, United States of America
Fetal alcohol exposure has deleterious consequences on the motor skills of patients affected by Fetal Alcohol Spectrum Disorder (FASD) and in pre-clinical models of gestational ethanol exposure (GEE). Deficits in striatal cholinergic interneurons (CINs) and dopamine function impair action learning and execution, yet the effects of GEE on acetylcholine (ACh) and striatal dopamine release remain unexplored. Here, we report that alcohol exposure during the first ten postnatal days (GEEP0-P10), which mimics ethanol consumption during the last gestational trimester in humans, induces sex-specific anatomical and motor skill deficits in female mice during adulthood. Consistent with these behavioral impairments, we observed increased stimulus evoked-dopamine levels in the dorsolateral striatum (DLS) of GEEP0-P10 female, but not male, mice. Further experiments revealed sex-specific deficits in β2-containing nicotinic ACh receptor (nAChR)-modulation of electrically evoked dopamine release. Moreover, we found a reduced decay of ACh transients and a decreased excitability of striatal CINs in DLS of GEEP0-P10 females, indicating striatal CIN dysfunctions. Finally, the administration of varenicline, a β2-containing nAChR partial agonist, and chemogenetic-mediated increase in CIN activity improved motor performance in adult GEEP0-P10 females. Altogether, these data shed new light on GEE-induced striatal deficits and establish potential pharmacological and circuit-specific interventions to ameliorate motor symptoms of FASD.
6:35pm - 6:55pmPrenatal THC exposure perturbates hippocampus-related cognitive functions in adolescent rats: is there a role for mitochondrial CB1 receptor?
Gianluca Lavanco1, Valentina Castelli1, Giuseppe Tringali2, Maria Elisabetta Clementi3, Patrizia Bottoni2, Anna Brancato1, Carla Cannizzaro1
1University of Palermo, Italy; 2University Cattolica del Sacro Cuore, Rome, Italy; 3Istituto di Scienze e Tecnologie Chimiche "Giulio Natta" SCITEC-CNR, Rome, Italy
Background: The endocannabinoid system is present at the early stages of development and represents a potential target for exogenous cannabinoids in utero. Indeed, the association between THC exposure during pregnancy and the risk for offspring neuropsychiatric disorders has been increasingly recognized over the past several years. Ample evidence implicates mitochondria in early brain development. However, among the mechanistic pathways through which maternal THC exposure may affect fetal brain development, mitochondria have received little attention.
Aim: We aim to address whether prenatal THC exposure may result in an aberrant developmental trajectory and produce long-lasting altered cognitive outcomes in the offspring and whether these abnormalities may also be reflected in mitochondrial bioenergetic function through the involvement of mtCB1Rs.
Methods: Following in utero THC exposure (2mg/kg delivered subcutaneously), offspring were assessed for neutral declarative memory in the Novel Object Recognition and spatial memory in Morris Water Maze. Then, combining molecular and bioenergetic analysis, mitochondrial functionality was evaluated, particularly the alterations of mitochondrial respiratory dynamics associated with the variations in oxygen consumption and activities of the mitochondrial respiratory chain related to prenatal THC exposure.
Results: In utero THC-exposed rats showed impaired neutral declarative memory, delayed spatial memory acquisition, and impaired spatial working memory. Interestingly, prenatally THC-exposed offspring displayed mitochondrial respiration impairment in the hippocampus and prefrontal cortex. No striking differences between the female and male offspring outcomes were observed, proving a sex-independent vulnerability.
Conclusion: This study provides fundamental insights into the aberrant cognitive processing induced by prenatal exposure to THC and proposes the mitochondrion as a subcellular intersection point connecting maternal THC exposure, brain development and cognitive functioning, besides as a potential site for therapeutic interventions.
6:55pm - 7:15pmPrenatal exposure to valproic acid in mice induces abnormal expression of Endogenous Retroviruses from intrauterine life to adulthood.
Chiara Cipriani1, Anna Maria Tartaglione2, Gemma Calamandrei2, Paola Sinibaldi-Vallebona1,3, Laura Ricceri2, Emanuela Balestrieri1
1Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy.; 2Centre for Behavioural Sciences and Mental Health, Istituto Superiore di Sanità, Rome, Italy.; 3Institute of Translational Pharmacology, National Research Council, Rome, Italy
Endogenous Retroviruses (ERVs), genetic elements originating from ancestral infection of germ line cells by exogenous retroviruses, are vertically transmitted from ancestors to descendants and currently constituting 8% and 10% of the human and mouse genome, respectively. Some ERVs have been co-opted for physiological functions, especially during pregnancy and embryogenesis. However, due to their responsiveness to environmental stimuli, copies of ERV can exhibit aberrant expression in several complex diseases, including Autism Spectrum Disorder (ASD). We highlighted a distinct expression profile of some Human ERV (HERV) families (HERV-H, -K and -W) in peripheral blood mononuclear cells from ASD children compared to controls, closely related with more severe clinical phenotype. Moreover, in a study including ASD children and their parents, we demonstrated that autistic children and their mothers share high expression levels of HERV-H, HEMO, cytokines as tumor necrosis factor alpha, interferon gamma and IL-10, suggesting a close mother–child association. This observation is in line with the results obtained in preclinical studies, in which prenatal exposure of CD-1 outbred mice to valproic acid (VPA) induced high expression levels of ERVs, proinflammatory cytokines and Toll-Like receptors starting from intrauterine life to adulthood. Notably, VPA exerted a direct and rapid effect on ERV activity already in embryos. Abnormal expression of ERV was maintained also after the birth, both in blood and brain tissues, but high levels, stable until adulthood, were observed only in the brain. Interestingly, in the valproate-treated mice, the increased expression of ERVs and behavioural alterations were inherited across generations via maternal lineage, further confirming a pivotal role of the maternal molecular profile in the acquisition of autistic phenotype. Although definitive proofs that ERVs are involved in neurobehavioral alterations are still lacking, both preclinical models and human studies indicate that the abnormal expression of ERVs could represent a neurodevelopmental disorders-associated biological trait.
7:15pm - 7:30pmEarly-life vs adulthood Fluoxetine-induced change of 5-HT homeostasis: distinct impact on behavior and serotonergic fiber wiring
Serena Nazzi1, Noemi Barsotti1, Giacomo Maddaloni2, Sara Migliarini1, Massimo Pasqualetti1
1University of Pisa, Italy; 2Harvard Medical School, Boston, MA, United States
The serotonergic system provides a profuse innervation to the whole central nervous system playing a critical role in disparate functions. The dysregulation of this system may cause the onset of psychiatric disorders. As already shown, genetically induced abrogation of 5-HT demonstrated that maintaining proper serotonin homeostasis in the adult brain is crucial to preserve the correct serotonergic axonal wiring. The change in 5-HT content reshape the serotonergic fibers that maintain a high level of structural plasticity even in adulthood. However, it is poorly investigated how 5-HT fibers respond to clinically relevant fluctuations in serotonin levels that may occur throughout an individual's life.
The aim of our work is to investigate whether serotonergic fibers can be remodeled by 5-HT fluctuation within the peri-physiological range and the effects on behaviour, when the oscillation occurs during or at the end of central nervous system development.
To this aim, we chronically treated Tph2GFP knock-in heterozygous mice, during adulthood or throughout development via the mother, with the SSRI fluoxetine a worldwide administered antidepressant drug also given to pregnant women due to its less side effects.
Here we demonstrated that chronic fluoxetine treatment during development causes the onset of a behavioural paradox increasing the anxiety- and depressive-like aspects.
Combining GFP immunofluorescence with confocal microscope imaging and 3D modeling analysis we showed that chronic fluoxetine exposure dramatically reduces the density of 5-HT fibers innervating the hippocampus.
We have also demonstrated that the serotonergic fiber density reduction is reversible when the treatment occurs in adulthood, while is permanent when the exposure is during development.
Taken together these data allow us to conclude that the adult serotonergic system is extremely plastic even in response to fluctuation in 5-HT within peri-physiological range, although the plasticity is permanently impaired whether the alteration in serotonin homeostasis occurs during central nervous system development.
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