SNAP-25 is a key component of the synaptic-vesicle fusion machinery, involved in 
several psychiatric diseases including schizophrenia and ADHD. SNAP-25 protein 
expression is lower in different brain areas of schizophrenic patients and in 
ADHD mouse models. How the reduced expression of SNAP-25 alters the properties 
of synaptic transmission, leading to a pathological phenotype, is unknown. We 
show that, unexpectedly, halved SNAP-25 levels at 13-14 DIV not only fail to 
impair synaptic transmission but instead enhance evoked glutamatergic 
neurotransmission. This effect is possibly dependent on presynaptic 
voltage-gated calcium channel activity and is not accompanied by changes in 
spontaneous quantal events or in the pool of readily releasable synaptic 
vesicles. Notably, synapses of 13-14 DIV neurons with reduced SNAP-25 expression 
show paired-pulse depression as opposed to paired-pulse facilitation occurring 
in their wild-type counterparts. This phenotype disappears with synapse 
maturation. As alterations in short-term plasticity represent a new mechanism 
contributing to cognitive impairments in intellectual disabilities, our data 
provide mechanistic clues for neuronal circuit alterations in psychiatric 
diseases characterized by reduced expression of SNAP-25.