Developing forebrain synapses are uniquely vulnerable to sleep loss.

Sleep is an essential behavior that supports lifelong brain health and cognition. Neuronal synapses are a major target for restorative sleep function and a locus of dysfunction in response to sleep deprivation (SD). Synapse density is highly dynamic during development, becoming stabilized with maturation to adulthood, suggesting sleep exerts distinct synaptic functions between development and adulthood. Importantly, problems with sleep are common in neurodevelopmental disorders including autism spectrum disorder (ASD). Moreover, early life sleep disruption in animal models causes long lasting changes in adult behavior. Different plasticity engaged during sleep necessarily implies that developing and adult synapses will show differential vulnerability to SD. To investigate distinct sleep functions and mechanisms of vulnerability to SD across development, we systematically examined the behavioral and molecular responses to acute SD between juvenile (P21-28), adolescent (P42-49) and adult (P70-100) mice of both sexes. Compared to adults, juveniles lack robust adaptations to SD, precipitating cognitive deficits in the novel object recognition test. Subcellular fractionation, combined with proteome and phosphoproteome analysis revealed the developing synapse is profoundly vulnerable to SD, whereas adults exhibit comparative resilience. SD in juveniles, and not older mice, aberrantly drives induction of synapse potentiation, synaptogenesis, and expression of peri-neuronal nets. Our analysis further reveals the developing synapse as a convergent node between vulnerability to SD and ASD genetic risk. Together, our systematic analysis supports a distinct developmental function of sleep and reveals how sleep disruption impacts key aspects of brain development, providing mechanistic insights for ASD susceptibility.

In Addition to Stigma: Cognitive and Autism-Related Predictors of Mental Health in Transgender Adolescents.

OBJECTIVE: Autism spectrum disorder (ASD) is significantly over-represented among transgender adolescents. Independently, ASD and gender diversity are associated with increased mental health risks. Yet, mental health in autistic-transgender adolescents is poorly understood. This study investigates mental health in the largest matched sample to date of autistic-transgender, non-autistic (allistic) transgender, and autistic-cisgender adolescents diagnosed using gold-standard ASD diagnostic procedures. In accordance with advancing understanding of sex/gender-related autism phenotypes, slightly subthreshold autistic diagnostic presentations (common in autistic girls/women) are modeled. METHOD: This study includes 93 adolescents aged 13-21, evenly divided between autistic-transgender, autistic-cisgender, and allistic-transgender groups; 13 transgender adolescents were at the margin of ASD diagnosis and included within a larger "broad-ASD" grouping. Psychological and neuropsychological evaluation included assessment of mental health, IQ, LGBT stigma, ASD-related social symptoms, executive functioning (EF), and EF-related barriers to achieving gender-related needs. RESULTS: Autistic-transgender adolescents experienced significantly greater internalizing symptoms compared to allistic-transgender and autistic-cisgender groups. In addition to stigma-related associations with mental health, ASD-related cognitive/neurodevelopmental factors (i.e., poorer EF and greater social symptoms) were associated with worse mental health: specifically, social symptoms and EF gender barriers with greater internalizing and EF problems and EF gender barriers with greater suicidality. Comparing across all ASD and gender-related groups, female gender identity was associated with greater suicidality. CONCLUSIONS: Parsing the heterogeneity of mental health risks among transgender youth is critical for developing targeted assessments and interventions. This study identifies ASD diagnosis, ASD phenotypic characteristics, and EF-related gender barriers as potential risks for poorer mental health in transgender adolescents.

Transgender Youth Executive Functioning: Relationships with Anxiety Symptoms, Autism Spectrum Disorder, and Gender-Affirming Medical Treatment Status.

Executive function (EF) underlies broad health and adaptive outcomes. For transgender youth, navigating gender discernment and gender affirmation demand EF. Yet, factors associated with transgender youth EF are unknown. We investigate hypothesized predictors of EF: over-represented conditions among transgender youth (anxiety and depression symptoms, autism spectrum disorder [ASD]) and gender-affirming care. One-hundred twenty-four transgender 11-21-year-olds participated. Parents/caregivers completed EF and mental health report measures. ASD diagnostics and gender-affirming medication histories were collected. 21 % of non-autistic and 69 % of autistic transgender youth had clinically elevated EF problems. Membership in the gender-affirming hormone treatment group was associated with better EF. ASD, anxiety symptoms, and membership in the long-duration pubertal suppression group were associated with poorer EF. Given the importance of EF skills for multiple outcomes, and the unique and additional EF demands specific to transgender youths' experiences, EF skill monitoring-and when appropriate, supports-should be considered for transgender youth.