Focal Clusters of Peri-Synaptic Matrix Contribute to Activity-Dependent Plasticity and Memory

Chelini, Gabriele; Mirzapourdelavar, Hadi; Durning, Peter; Baidoe-Ansah, David; O’Donovan, Sinead M.; Klengel, Torsten; Balasco, Luigi; Berciu, Cristina; Boyer-Boiteau, Anne; Smith, Robert A.; Ressler, Kerry J.; Bozzi, Yuri; Dityatev, Alexander; Berretta, Sabina

doi:10.2139/ssrn.4512954

Cited by 1 publication

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“…Lack of synaptic turnover within the BLA may underlie a deteriorated signal-to-noise ratio within the amygdala microcircuitry, determining an over-generalization of behavioral strategies irrespectively to the biological valence of the surrounding environment. In support of this hypothesis, a previous study show that organized synaptic ensembles identified by immunolabeling of 6-sulfated chondroitin sulfate (41) are reduced in the postmortem brain of people with BD (42), suggesting that the lack of locally organized plasticity may contribute to BD pathology. In line with this hypothesis, we interrogated the microglia phenotype within the BLA of the same mice showing altered synaptic phenotype.…”

Section: Discussionmentioning

confidence: 76%

Early-life scarcity adversity biases behavioral development toward a bipolar-like phenotype in mice heterozygous for CNTNAP2

Chelini,

Fortunato-Asquini,

Cerilli

et al. 2024

Preprint

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The etiological complexity of psychiatric disorders arises from the dynamic interplay between genetic and environmental vulnerabilities. Among the environmental components, early-life adversities (ELA) are a major risk-factors for developing a psychiatric disorder. Yet, the mechanistic interaction between ELA and genetic vulnerability contributing to psychopathology is poorly understood. To fill this gap, we took advantage of the ideally controlled conditions of a pre-clinical approach. In this study we raised a mouse model with genetic predisposition to multiple psychiatric disorders (autism spectrum, schizophrenia, bipolar disorder), the Cntnap2+/- mouse, with limited bedding and nesting (LBN), a well-established paradigm to induce early-life stress in rodents. These mice were compared to LBN-raised Cntnap2+/+ littermates, as well as parallel groups of Cntnap2+/+ and Cntnap2+/- raised in standard conditions. Using a battery for behavioral phenotyping we show that ELA shapes non-overlapping phenotypic landscapes based on genetic predisposition. Specifically, we found that LBN-raised Cntnap2+/- mice develop a perseverative risk-taking behavior in the elevated plus maze and that this behavior is highly predictive of their success in the social interaction, assessed with the 3-chamber test. This finding suggests that the intrusion of anxiety into the social behavioral domain contributes to extreme gain- or loss-of function in social interaction, resembling a bipolar-like phenotype. Finally, we show that LBN promotes synaptic hypertrophy in the basolateral nucleus of the amygdala, but only in Cntnap2+/- raised in LBN this condition was found in combination with microglia abnormalities. We conclude that the interplay between ELA and Cntnap2 haploinsufficiency exacerbates bipolar-like behaviors in mice, and that this may be consequence of deficient synaptic homeostasis in the basolateral amygdala.

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Section: Discussionmentioning

confidence: 76%