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The special AT-rich sequence-binding protein 2 (SATB2) is associated with human cognitive ability. Mutations in the SATB2 gene lead to SATB2-associated syndrome (SAS), characterized by severe intellectual disability. SATB2 is mainly expressed in pyramidal neurons in the cerebral cortex and hippocampus, playing a crucial role in cognitive processes. However, the function of SATB2 in the adult hippocampus remains unclear. In this study, we deleted Satb2 in the CA1 region of the adult mouse hippocampus and observed cognitive impairments along with significant changes in soma and dendrite morphology. Additionally, we identified the growth factor pleiotrophin (PTN) as a downstream target of Satb2, essential for mediating its impact on cognitive functions. Importantly, increasing PTN expression mitigated the morphological and behavioral deficits resulting from Satb2 deletion in CA1. Our findings highlight the importance of hippocampal Satb2 in regulating cognitive function in adult mice through PTN modulation.