Complexins (CPLXs) are small isomeric proteins that bind to the soluble NSF-attachment protein receptor (SNARE) complex and modulate neurotransmitter release. Two isoforms of CPLX exist in the brain, CPLXI and CPLXII. These are differentially distributed in the cortex and cerebellum, with CPLXI found in axosomatic terminals and CPLXII in axodendritic terminals. Since in cortex and cerebellum axosomatic terminals are inhibitory and axodendritic terminals are excitatory, it has been assumed that CPLXI modulates inhibitory and CPLXII modulates excitatory transmitter release. Here we used in situ hybridisation to study the mRNA distribution of CPLXI and CPLXII in mouse brain. We show that while CPLXs are expressed in distinct cell populations, they do not segregate with either particular neurotransmitters, or different classes of transmitter action. For example, while CPLXII is the dominant isoform in the output (glutamatergic excitatory) neurons of the cortex, it is also the dominant isoform in medium spiny (GABAergic inhibitory) neurons of the striatum. We suggest that the functional role of CPLXs depends not only on the identity of the neurotransmitter, but also upon the circuitry connecting the neurons in which they are expressed. Thus, the predominant expression of CPLXII in neurons of the basal ganglia and cortex suggests a role in cognition, emotional behaviour and control of voluntary movement, while the pattern of CPLXI expression suggests a primary role in motor learning programs and sensory processing. (C) 2004 Elsevier Inc. All rights reserved.