SATB2 is a schizophrenia risk gene and is genetically associated with human intelligence. How it affects cognition at molecular level is currently unknown. Here, we show that interactions between SATB2, a chromosomal scaffolding protein, and the inner nuclear membrane protein LEMD2 orchestrate the response of pyramidal neurons to neuronal activation. Exposure to novel environment in vivo causes changes in nuclear shape of CA1 hippocampal neurons via a SATB2‐dependent mechanism. The activity‐driven plasticity of the nuclear envelope requires not only SATB2, but also its protein interactor LEMD2 and the ESCRT‐III/VPS4 membrane‐remodeling complex. Furthermore, LEMD2 depletion in cortical neurons, similar to SATB2 ablation, affects neuronal activity‐dependent regulation of multiple rapid and delayed primary response genes. In human genetic data, LEMD2‐regulated genes are enriched for de novo mutations reported in intellectual disability and schizophrenia and are, like SATB2‐regulated genes, enriched for common variants associated with schizophrenia and cognitive function. Hence, interactions between SATB2 and the inner nuclear membrane protein LEMD2 influence gene expression programs in pyramidal neurons that are linked to cognitive ability and psychiatric disorder etiology. SYNOPSIS: Cognitive processes depend on gene transcription in pyramidal neurons, which is stimulated by neuronal activity. Here, the interactions between the chromosomal scaffold protein SATB2, the inner nuclear membrane protein LEMD2, and the ESCRT‐III/VPS4 machinery are shown to orchestrate these activity‐dependent gene transcription and nuclear shape changes. SATB2, LEMD2 and ESCRT‐III/VPS4 are required for synaptic activity‐triggered nuclear membrane remodelling in pyramidal neurons.Both LEMD2 depletion and Satb2 ablation disrupts neuronal activity‐dependent gene expression.In humans, orthologues of LEMD2‐regulated genes in mouse cortical neurons are enriched for de novo mutations reported in intellectual disability and schizophreniaLEMD2‐ and SATB2‐regulated genes are also enriched for common variants associated with schizophrenia and cognitive function. [ABSTRACT FROM AUTHOR]