HnRNPH2-related neurodevelopmental disorder (NDD) is caused by mutations in the HNRNPH2 gene and is associated with substantial challenges, including developmental delay, intellectual disability, growth delay, and epilepsy. There is currently no therapeutic intervention available to those with hnRNPH2-related NDD that addresses its underlying mechanisms. In this issue of the JCI, Korff et al. studied specific gain-of-function mutations associated with hnRNPH2-related NDD, with the help of mouse models that recapitulate key features of the condition in humans. Their work paves the way for therapeutic approaches that aim to reduce the expression of mutant hnRNPH2 and highlights a role for disrupted RNA granules in neurodevelopmental and neurodegenerative disorders.

Biological sex shapes the manifestation and progression of neurodevelopmental disorders (NDDs), however, the underlying mechanisms remains unclear. Hemideletion of the 16p11.2 region (16p11.2 del/+) is associated with NDDs, and 16p11.2 del/+ mice exhibit sex-specific, striatum-related phenotypes relevant to NDDs. In this study, using snRNA-seq, we identify cell type- and sex-specific transcriptomic changes in D1- and D2-spiny projection neurons (SPNs), with greater impact in males. Fiber photometry recordings reveal reduced neuronal activity in the dorsal striatum of 16p11.2 del/+ males, but not females, with D2-SPNs identified as the primary contributors to this reduction. Behaviorally, we utilize conditional genetic approaches and find that selective hemideletion in D2-SPNs, but not D1-SPNs, induces male-specific hyperactivity, whereas cortical hemideletion increases hyperactivity in both sexes. Thus, a locus linked to NDDs acts in distinct striatal circuits, selectively impacting behavior in a sex- and cell type-specific manner.

Biological sex shapes the manifestation and progression of neurodevelopmental disorders (NDDs). These disorders often demonstrate male-specific vulnerabilities; however, the identification of underlying mechanisms remains a significant challenge in the field. Hemideletion of the 16p11.2 region (16p11.2 del/+) is associated with NDDs, and mice modeling 16p11.2 del/+ exhibit sex-specific striatum-related phenotypes relevant to NDDs. Striatal circuits, crucial for locomotor control, consist of two distinct pathways: the direct and indirect pathways originating from D1 dopamine receptor (D1R) and D2 dopamine receptor (D2R) expressing spiny projection neurons (SPNs), respectively. In this study, we define the impact of 16p11.2 del/+ on striatal circuits in male and female mice. Using snRNA-seq, we identify sex- and cell type-specific transcriptomic changes in the D1- and D2-SPNs of 16p11.2 del/+ mice, indicating distinct transcriptomic signatures in D1-SPNs and D2-SPNs in males and females, with a ∼5-fold greater impact in males. Further pathway analysis reveals differential gene expression changes in 16p11.2 del/+ male mice linked to synaptic plasticity in D1- and D2-SPNs and GABA signaling pathway changes in D1-SPNs. Consistent with our snRNA-seq study revealing changes in GABA signaling pathways, we observe distinct changes in miniature inhibitory postsynaptic currents (mIPSCs) in D1- and D2-SPNs from 16p11.2 del/+ male mice. Behaviorally, we utilize conditional genetic approaches to introduce the hemideletion selectively in either D1- or D2-SPNs and find that conditional hemideletion of genes in the 16p11.2 region in D2-SPNs causes hyperactivity in male mice, but hemideletion in D1-SPNs does not. Within the striatum, hemideletion of genes in D2-SPNs in the dorsal lateral striatum leads to hyperactivity in males, demonstrating the importance of this striatal region. Interestingly, conditional 16p11.2 del/+ within the cortex drives hyperactivity in both sexes. Our work reveals that a locus linked to NDDs acts in different striatal circuits, selectively impacting behavior in a sex- and cell type-specific manner, providing new insight into male vulnerability for NDDs. Highlights - 16p11.2 hemideletion (16p11.2 del/+) induces sex- and cell type-specific transcriptomic signatures in spiny projection neurons (SPNs). - Transcriptomic changes in GABA signaling in D1-SPNs align with changes in inhibitory synapse function. - 16p11.2 del/+ in D2-SPNs causes hyperactivity in males but not females. - 16p11.2 del/+ in D2-SPNs in the dorsal lateral striatum drives hyperactivity in males. - 16p11.2 del/+ in cortex drives hyperactivity in both sexes.

The complement system is a major component of the innate immune system and plays an important role in immune surveillance. Recent research has demonstrated that the complement system also plays pivotal roles in brain development, and dysregulation of complement is involved in neurodegenerative and neuropsychiatric disorders. However, the mechanisms by which the complement system contributes to neurodevelopmental disorders (NDDs) remain poorly understood. In this study, we find that the expression of a central regulator of the complement cascade, complement component 3 (C3), is upregulated in the striatum of mice modeling the 16p11.2 hemideletion (16p11.2 del). 16p11.2 del is among the most common copy number variations associated with NDDs including attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and intellectual disability (ID). Pharmacological inhibition of the C3a receptor alleviates hyperactivity in 16p11.2 del mice, suggesting that elevated complement contributes to NDD-relevant behavioral changes. Due to the pro-inflammatory actions of the C3a receptor, we assess the cytokine environment in the striatum, a key neural substrate for locomotor behavior, and find that several inflammatory factors are upregulated in 16p11.2 del mice. Collectively, these results indicate that increased expression of the complement system, especially C3, mediates hyperactive behavior and is associated with a pro-inflammatory environment in the striatum of 16p11.2 del mice. Our results suggest that inhibition of an overactive complement system may be an effective strategy to ameliorate NDD symptoms resulting from 16p11.2 hemideletion including those associated with ADHD.