hnRNPH2 gain-of-function mutations reveal therapeutic strategies and a role for RNA granules in neurodevelopmental disorders.

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.

Sterol dysregulation in Smith-Lemli-Opitz syndrome causes astrocyte immune reactivity through microglia crosstalk.

Owing to the need for de novo cholesterol synthesis and cholesterol-enriched structures within the nervous system, cholesterol homeostasis is critical to neurodevelopment. Diseases caused by genetic disruption of cholesterol biosynthesis, such as Smith-Lemli-Opitz syndrome, which is caused by mutations in 7-dehydrocholesterol reductase (DHCR7), frequently result in broad neurological deficits. Although astrocytes regulate multiple neural processes ranging from cell migration to network-level communication, immunological activation of astrocytes is a hallmark pathology in many diseases. However, the impact of DHCR7 on astrocyte function and immune activation remains unknown. We demonstrate that astrocytes from Dhcr7 mutant mice display hallmark signs of reactivity, including increased expression of glial fibrillary acidic protein (GFAP) and cellular hypertrophy. Transcript analyses demonstrate extensive Dhcr7 astrocyte immune activation, hyper-responsiveness to glutamate stimulation and altered calcium flux. We further determine that the impacts of Dhcr7 are not astrocyte intrinsic but result from non-cell-autonomous effects of microglia. Our data suggest that astrocyte-microglia crosstalk likely contributes to the neurological phenotypes observed in disorders of cholesterol biosynthesis. Additionally, these data further elucidate a role for cholesterol metabolism within the astrocyte-microglia immune axis, with possible implications in other neurological diseases.

Neurobiological insights into twice-exceptionality: Circuits, cells, and molecules.

Twice-exceptional learners face a unique set of challenges arising from the intersection of extraordinary talent and disability. Neurobiology research has the capacity to complement pedagogical research and provide support for twice-exceptional learners. Very few studies have attempted to specifically address the neurobiological underpinnings of twice-exceptionality. However, neurobiologists have built a broad base of knowledge in nervous system function spanning from the level of neural circuits to the molecular basis of behavior. It is known that distinct neural circuits mediate different neural functions, which suggests that 2e learning may result from enhancement in one circuit and disruption in another. Neural circuits are known to adapt and change in response to experience, a cellular process known as neuroplasticity. Plasticity is controlled by a bidirectional connection between the synapse, where neural signals are received, and the nucleus, where regulated gene expression can return to alter synaptic function. Complex molecular mechanisms compose this connection in distinct neural circuits, and genetic alterations in these mechanisms are associated with both memory enhancements and psychiatric disorder. Understanding the consequences of these changes at the molecular, cellular, and circuit levels will provide critical insights into the neurobiological bases of twice-exceptionality.