Prenatal exposure to the antiepileptic drug valproic acid (VPA) induces autism spectrum disorder (ASD) in humans and autistic-like behaviors in rodents, which makes it a good model to study the neural underpinnings of ASD. Rats prenatally exposed to VPA show profound deficits in the social domain. The altered social behavior displayed by VPA-exposed rats may be due to either a deficit in social reward processing or to a more general inability to properly understand and respond to social signals. To address this issue, we performed behavioral, electrophysiological and neurochemical experiments and tested the involvement of the brain reward system in the social dysfunctions displayed by rats prenatally exposed to VPA (500 mg/kg). We found that, compared to control animals, VPA-exposed rats showed reduced play responsiveness together with impaired sociability in the three-chamber test and altered social discrimination abilities. In addition, VPA-exposed rats showed altered expression of dopamine receptors together with inherent hyperexcitability of medium spiny neurons (MSNs) in the nucleus accumbens (NAc). However, when tested for socially-induced conditioned place preference, locomotor response to amphetamine and sucrose preference, control and VPA-exposed rats performed similarly, indicating normal responses to social, drug and food rewards. On the basis of the results obtained, we hypothesize that social dysfunctions displayed by VPA-exposed rats are more likely caused by alterations in cognitive aspects of the social interaction, such as the interpretation and reciprocation of social stimuli and/or the ability to adjust the social behavior of the individual to the changing circumstances in the social and physical environment, rather than to inability to enjoy the pleasurable aspects of the social interaction. The observed neurochemical and electrophysiological alterations in the NAc may contribute to the inability of VPA-exposed rats to process and respond to social cues, or, alternatively, represent a compensatory mechanism towards VPA-induced neurodevelopmental insults.

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We investigated the molecular events triggered by NMDA and 3,5-dihydroxyphenylglycine (DHPG) preconditioning, that lead to neuroprotection against excitotoxic insults (AMPA or oxygen and glucose deprivation) in rat organotypic hippocampal slices, with particular attention on glutamate receptors and on cannabinoid system. We firstly evaluated the protein expression of NMDA and AMPA receptor subunits after preconditioning using western blot analysis performed in post-synaptic densities. We observed that following NMDA, but not DHPG preconditioning, the expression of GluA1 was significantly reduced and this reduction appeared to be associated with the internalization of AMPA receptors. Whole-cell voltage clamp recordings on CA1 pyramidal neurons of organotypic slices show that 24 hr after exposure to NMDA and DHPG preconditioning, AMPA-induced currents were significantly reduced. To clarify the mechanisms induced by DHPG preconditioning, we then investigated the involvement of the endocannabinoid system. Exposure of slices to the CB1 antagonist AM251 prevented the development of tolerance to AMPA toxicity induced by DHPG but not NMDA. Accordingly, the MAG-lipase inhibitor URB602, that increases arachidonoylglycerol (2-AG) content, but not the FAAH inhibitor URB597, that limits the degradation of anandamide, was also able to induce tolerance versus AMPA and OGD toxicity, suggesting that 2-AG is responsible for the DHPG-induced tolerance. In conclusion, preconditioning with NMDA or DHPG promotes differential neuroprotective mechanisms: NMDA by internalization of GluA1-AMPA receptors, DHPG by producing the endocannabinoid 2-AG.

Cannabidiol (CBD), one of the main components of cannabis, is generally considered safe. CBD crosses the placenta and its use during pregnancy is steadily increasing, the impact of gestational CBD’s effects on prenatal life and neurodevelopment are poorly understood. Here, we combined behavioral approaches and deep learning analysis to assess the sex-dependent neonatal behavior of CBD exposed progeny. Gestating C57BL6/J dams were exposed daily with vehicle or CBD (3 mg/Kg, s.c.), from gestational day 5 to 18. Body weight, pup ultrasound vocalizations (USVs, PND 10) and homing behavior (PND 13) were quantified in the progeny. Thus, male (but not female) pups from CBD-treated dams gained more weight than sham. There were sex-dependent differences in the coarse characteristics of ultrasonic vocalizations. Prenatally-CBD exposed male pups emitted shorter calls, whereas CBD females made more high frequency calls when compared with their control counterparts. There were significant qualitative changes in the syllabic USV repertoire reflected in call typologies and communication patterns. Finally, the homing behavior test showed that CBD-exposed females presented a greater vulnerability to gestational CBD than males. Only CBD-exposed female pups showed reduced motor and discriminatory abilities. Together the results suggest a sexual divergence in the consequences of in utero CBD exposure on neonates at early developmental ages, which may be predictive of adult psychopathology. Given the extent of cannabis and CBD use worldwide, these findings challenge the idea that CBD is a universally safe compound and reveal the need for additional studies on the effect of perinatal CBD exposure.

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Pup-dam ultrasonic vocalizations (USVs) contribute to the formation of neural circuits and behaviors essential for standard cognitive and socio-emotional development. In conditions like autism and Fragile X Syndrome (FXS), disruptions in pup-dam USV communication hint at a possible connection between abnormal early developmental USV communication and the later emergence of communication and social deficits. Syntax, a crucial element of rodent "language," has rarely been investigated in FXS mice, let alone in specimens of both sexes. Therefore, in this study, we gathered USVs from PND 10 FXS pups during a short period of separation from their mothers, encompassing animals of all possible genotypes and both sexes (i.e., Fmr1-/yvs. Fmr1+/y males and Fmr1+/+, +/-, and -/-females). This allowed us to compare, for the first time, the relative influence of sex and gene dosage on their communication capabilities. Leveraging DeepSqueak and analyzing vocal patterns, we examined intricate vocal behaviors such as call structure, duration, frequency modulation, and temporal patterns. The results demonstrate that FMRP-deficient pups of both sexes display an increased inclination to vocalize when separated from their mothers, and this behavior is accompanied by significant sex-specific changes in the main features of their USVs as well as in body weight. Moreover, the decoding of the vocal repertoire and its syntactic usage revealed that the silencing of the Fmr1 gene primarily alters the qualitative composition of ultrasonic communication in males. These findings highlight the fascinating interplay between Fmr1 gene dosage and sex in shaping communication during infancy.

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