2026 Volume 49 Issue 9 Pages 1395-1403
Nuclear bodies are membrane-less compartments formed via liquid-liquid phase separation (LLPS) and serve as “dynamic information-processing hubs” for key molecular processes, including transcription and RNA metabolism. In the nervous system, these functional condensates provide a physical substrate for the formation of diverse splicing isoforms, which are essential for maintaining the complexity of the human brain. Recent findings suggest that the collapse of this “nuclear infrastructure” is the underlying cause of several psychiatric disorders. This collapse is due to an aberrant phase transition, where the nuclear environment shifts from a reversible, dynamic state to an irreversible, rigid state—a disruption of the homeostatic mechanism known as “Interstasis.” This review discusses how this physical transition leads to systemic splicing failure and explores next-generation therapeutic strategies, such as antisense oligonucleotides (ASOs) and small-molecule modifiers, to restore nuclear integrity. This review is structured as follows to systematically explore the nexus between subnuclear architecture and neuropsychiatric pathogenesis. Section 1 establishes the biophysical foundations of nuclear bodies, highlighting LLPS and homeostatic mechanisms like interstasis. Section 2 addresses the advanced diversity and spatiotemporal regulation of alternative splicing in the nervous system, with a particular focus on the neuron-specific long non-coding RNA Gomafu. Section 3 comprehensively dissects the molecular mechanisms of nuclear infrastructure collapse—encompassing aberrant phase transitions, microexon/novel exon dysregulation, and 3D genome and transport deficits—in neurodevelopmental disorders and schizophrenia. Finally, Section 4 outlines next-generation drug discovery strategies, focusing on therapeutic modalities such as ASOs and small molecules capable of modulating network-level analog states.
