Striking correlations exist between the abilities of domain-1 cleft mutants of Munc18-1 to bind and chaperone syntaxin-1 and their ability to restore vesicle docking and secretion.

e Deletion of the LIMK1 gene is associated with Williams syndrome, a unique neurodevelopmental disorder characterized by severe defects in visuospatial cognition and long-term memory (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 critical 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 with Williams syndrome through the enhancement of CREB activity in the adult brain.

Highlights d Splicing of the GluN1 exon 5-encoded N1 cassette alters allosteric modulation in vivo d Synapses of N1-containing NMDARs show reduced longterm potentiation d Mice lacking the N1 cassette have improved spatial memory acquisition and recall d iPSC-derived neurons in autism spectrum disorder show traits of N1-lacking GluN1

Voa1 and Voa2 cooperatively regulate the acidification and transmitter uptake/storage of dense-core vesicles, although they might not be as critical for exocytosis as recently proposed.

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