Compromised placental function or premature loss has been linked to diverse neurodevelopmental disorders. Here we show that placenta allopregnanolone (ALLO), a progesterone-derived GABA-A receptor (GABA_AR) modulator, reduction alters neurodevelopment in a sex-linked manner. A new conditional mouse model, in which the gene encoding ALLO’s synthetic enzyme (akr1c14) is specifically deleted in trophoblasts, directly demonstrated that placental ALLO insufficiency led to cerebellar white matter abnormalities that correlated with autistic-like behavior only in male offspring. A single injection of ALLO or muscimol, a GABA_AR agonist, during late gestation abolished these alterations. Comparison of male and female human preterm infant cerebellum also showed sex-linked myelination marker alteration, suggesting similarities between mouse placental ALLO insufficiency and human preterm brain development. This study reveals a new role for a placental hormone in shaping brain regions and behaviors in a sex-linked manner. Placental hormone replacement might offer novel therapeutic opportunities to prevent later neurobehavioral disorders.

Placental endocrine function is essential to fetal brain development. Placental hormones include neurosteroids such as allopregnanolone (ALLO), a regulator of neurodevelopmental processesviapositive allosteric modulation of the GABA_Areceptor (GABA_A-R). Using a mouse model (plKO) in which the gene encoding the ALLO synthesis enzyme is specifically deleted in trophoblasts, we previously showed that placental ALLO insufficiency alters cerebellar white matter development and leads to male-specific autistic-like behavior. We now demonstrate that the lack of placental ALLO causes female-predominant alterations of cortical development and function. Placental ALLO insufficiency disrupts cell proliferation in the primary somatosensory cortex (S1) in a sex-linked manner. Early changes are seen in plKO embryos of both sexes, but persist primarily in female offspring after birth. Adolescent plKO females show significant reduction in pyramidal neuron density, as well as somatosensory behavioral deficits as compared with plKO males and control littermates. Assessment of layer-specific markers in human postmortem cortices suggests that preterm infants may also have female-biased abnormalities in cortical layer specification as compared with term infants. This study establishes a novel and fundamental link between placental function and sex-linked long-term neurological outcomes, emphasizing the importance of the growing field of neuroplacentology.

The placenta is a fetal endocrine organ that secretes many neuroactive factors, including steroids, that play critical roles in brain development. The study of the placenta‐brain axis and the links between placental function and brain development represents an emerging research area dubbed “neuroplacentology.” The placenta drives many circulating fetal steroids to very high levels during gestation. Recent studies have highlighted the critical role of placental steroids in shaping specific brain structures and behaviors. This review uses a cross‐species framework to discuss the genomic factors, in‐utero environmental changes, and placental conditions that alter placental steroidogenesis, leading to changes in early developmental trajectories relevant for psychiatric conditions such as autism, in a sex‐linked manner.

Preterm birth substantially elevates the risk of neurological and cognitive disorders. Recent evidence suggests that the abrupt loss of placental support, particularly the cessation of neurotrophic and neuroprotective hormones, alters neurodevelopmental trajectories and may contribute to neurodevelopmental risk associated with prematurity. Our study investigates how the placental steroid hormone, allopregnanolone (ALLO), affects cerebral cortex development using human cortical organoid models. Our findings reveal that while ALLO exposure produces modest effects on overall cortical development, its withdrawal specifically disrupts GABAergic but not glutamatergic neuronal development. These results demonstrate that placental hormones, including ALLO, may target specific neuronal populations critical for cortical function, identifying potential therapeutic interventions following placental loss in human preterm neonates.

Down syndrome is the most common genetic cause of intellectual disability. Individuals face elevated risks for epilepsy and early-onset Alzheimer's, yet effective treatments for cognitive impairments remain unavailable. The Ts65Dn mouse, featuring a segmental trisomy of distal chromosome 16, serves as the primary experimental system for studying underlying mechanisms. Excitation-inhibition imbalance is considered as a key contributor to the learning and memory deficits in Down syndrome. Ts65Dn mice show heightened dentate gyrus miniature IPSC frequency and enhanced GABAA-and GABAB-receptor-mediated IPSCs, but which interneuron subtypes drive this excess inhibition was unknown. Using optogenetic, electrophysiological, and histological approaches, Gutmann et al. revealed complex inhibitory dysregulation in the Ts65Dn dentate gyrus. Their study suggests excitation-inhibition imbalance in Down syndrome involves redistribution of inhibitory control along the dendritic axis rather than a global shift and highlights differential effects across interneuron subtypes in neurodevelopmental disorders.A notable theme emerging from this collection is the sex-specific vulnerability of interneurons to pathological insults. Consumi et al. demonstrate that traumatic brain injury produces markedly different effects in the hippocampus of male versus female rodents. Females show greater interneuron loss and elevated pro-apoptotic signaling yet display more transient cognitive deficits than males. Males exhibit sustained cognitive impairments associated with reduced pro-survival mechanisms. This dissociation between cellular pathology and functional outcomes challenges simplistic models of interneuron dysfunction and underscores an urgent need for sex-informed therapeutic strategies that recognize distinct mechanistic pathways converging on similar behavioral phenotypes.In schizophrenia, interneuron dysfunction shows subtype-specific patterns that impair working memory. Hughes et al. review the molecular and cellular alterations in interneuron pathology in schizophrenia, focusing on the dorsolateral prefrontal cortex, a region critical for working memory. Their analysis reveals a nuanced picture of subtype-specific alterations: some interneuron subtypes show reduced markers suggesting decreased functionality, while others are relatively spared. These changes occur alongside broader GABAergic dysfunction that collectively impairs neural synchronization underlying working memory. Importantly, Hughes et al. note that affective disorders including bipolar disorder and major depressive disorder show inconsistent interneuron pathology, with region-and layer-specific effects that differ from schizophrenia, suggesting that while these conditions share cognitive symptoms, their underlying circuit-level mechanisms may diverge. Elucidating the precise nature of GABAergic abnormalities (including direct measurement of GABA levels in human brain tissue) and their consequences for neural circuit dysfunction in schizophrenia remains essential for designing therapeutics that target specific interneuron subtypes and restore functional network dynamics.Fu and Tasker add another dimension by examining how neuromodulatory systems regulate interneuron function in the basolateral amygdala (BLA) during emotional states. In this region, stress-induced anxiety involves interactions between glucocorticoid and endocannabinoid signaling at inhibitory synapses. This review describes how multiple neuromodulators converging on Gq-coupled signaling pathways produce cell type-specific activity patterns. These activation patterns, generalizable across different neurotransmitters and receptors, represent a fundamental mechanism for tuning BLA network oscillations and fear expression. The findings challenge the common assumption that Gq-coupled Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) simply increase neural excitability. Instead, neuromodulation introduces specific patterns of network activation that may reflect different operational modes of circuit function.Zerlaut and Tzilivaki offer a fresh perspective on cortical inhibition, proposing that beyond their classical roles in network stability and temporal precision, certain interneuron subtypes act as computational switches, dynamically reconfiguring how cortical circuits process information. Drawing on experimental and theoretical evidence from rodent sensory cortices, they argue that interneuron dysfunction may impair this computational flexibility, contributing to neurodevelopmental and psychiatric disorders. They highlight emerging evidence that specific interneuron subtypes possess sophisticated dendritic integration and plasticity properties. Understanding these cell-type-specific mechanisms will be essential for developing targeted interventions that restore adaptive circuit function in disease.Using human cortical organoid technology, Lacaille et al. demonstrate that withdrawal of the placental neurosteroid allopregnanolone selectively disrupts GABAergic interneuron development while leaving glutamatergic neurons largely unaffected. This cell type-specific vulnerability provides a mechanistic explanation for the increased neurodevelopmental risk observed in preterm infants, who experience abrupt cessation of placental ALLO support weeks before term. The organoid platform not only allows to study disease mechanisms but also provides an experimental system for testing candidate interventions and dissecting their cellular and molecular mechanisms in human tissue.These contributions advance understanding of interneuron pathophysiology in three critical ways. First, interneuron dysfunction involves subtype-specific, region-specific, and sex-specific alterations. Second, functional consequences depend on how alterations affect network dynamics and computational properties, not just cell loss or molecular changes. Third, neuromodulatory systems dynamically...

Background: Differences in extracellular vesicles (EVs), bioactive nanoparticles involved in intercellular signaling, have been reported in those with autism. However, little is known about the association between maternal EVs during pregnancy and the likelihood of autism in offspring. This study evaluated the association of the concentration and cargo material of EVs in prenatal maternal plasma with childhood autism likelihood. Methods: Participants in the Nulliparous Pregnancy Outcomes Study provided maternal plasma at 15–23 weeks’ gestational age. EVs were isolated by ultracentrifugation, and concentration, mean size, CD63 levels, and RNA cargo were assessed by nanoparticle tracking analysis, ELISA, and small RNA sequencing. At 4.5–6 years of age, parents completed the Social Communication Questionnaire. Thirty-one children at high-risk for autism were matched to 31 low-risk children on sex, age, and gestational age. Differential RNA transcript analysis and over representation analysis were performed. Results: There were no group differences in CD63 levels, mean particle size, or EV concentration ( p >0.1). Nominal bin-level differences were observed at 280–290 nm and 430–440 nm before multiple-comparison correction. One hundred forty-five RNAs, including protein-coding RNAs, piRNAs, lncRNAs, miRNAs, snoRNAs, snRNAs, and tRNAs, were differentially contained, most of them downregulated in those at high risk of autism. These RNAs mapped to pathways involved in immune/inflammatory signaling, intracellular trafficking, protein turnover, and neurodevelopment. Six of the 62 (9.7%) differentially contained protein-coding RNAs overlapped with genes in the SFARI Gene database. Limitations: Large studies involving individuals diagnosed with autism are needed to evaluate the role of prenatal EVs in the pathogenesis of the condition. Additionally, prenatal sampling of EVs across multiple timepoints and subsequent deconvolution to determine the source of the EVs will strengthen interpretability and veracity of our findings. Conclusions: These findings provide preliminary evidence that maternal prenatal EV RNA cargo is associated with childhood autism likelihood.