LIMK1 Regulates Long-Term Memory and Synaptic Plasticity via the Transcriptional Factor CREB

Deletion of the LIMK1 gene is associated withWilliams syndrome, a unique neurodevelopmental disorder characterized by se-vere defects in visuospatial cognition and long-termmemory (LTM). However, whether LIMK1 contributes to these deficits remains elusive. Here, we show that LIMK1-knockout (LIMK1/) mice are drastically impaired in LTM but not short-term memory (STM). In addition, LIMK1/mice are selectively defective in late-phase long-term potentiation (L-LTP), a form of long-lasting synaptic plasticity specifically required for the formation of LTM. Furthermore, we show that LIMK1 interacts and regulates the activity of cyclic AMP response element-binding protein (CREB), an extensively studied transcriptional factor criti-cal for LTM. Importantly, both L-LTP and LTM deficits in LIMK1/mice are rescued by increasing the activity of CREB. These results provide strong evidence that LIMK1 deletion is sufficient to lead to an LTM deficit and that this deficit is attributable to CREB hypofunction. Our study has identified a direct gene-phenotype link in mice and provides a potential strategy to restore LTM in patients withWilliams syndrome through the enhancement of CREB activity in the adult brain. Williams syndrome (WS) is a neurodevelopmental disordercaused by the hemizygous deletion of a 1.5-million-bp seg-ment of human chromosome 7q11.23 (1). Although individuals with WS have global cognitive impairments, they demonstrate a consistent pattern of strengths and weaknesses characterized by a relatively preserved concrete vocabulary and verbal short-ter