Schizophrenia is a devastating disease that affects approximately 1% of the population across cultures. Its neurobiological underpinnings are still unknown. Accordingly, animal models of schizophrenia often lack construct validity. As concordance rate in monozygotic twins amounts to only 50%, environmental risk factors (e.g. neurotrauma, drug abuse, psychotrauma) likely act as necessary 'second hit' to trigger/drive the disease process in a genetically predisposed individual. Valid animal models would have to consider this genetic-environmental interaction. Based on this concept, we designed an experimental approach for modeling a schizophrenia-like phenotype in mice. As dysfunction in synaptic transmission plays a key role in schizophrenia, and complexin2 (CPLX2) gene expression is reduced in hippocampus of schizophrenic patients, we developed a mouse model with Cplx2 null mutation as genetic risk factor and a mild parietal neurotrauma, applied during puberty, as environmental 'second hit'. Several months after lesion, Cplx2 null mutants showed reduced pre-pulse inhibition, deficit of spatial learning and loss of inhibition after MK-801 challenge. These abnormalities were largely absent in lesioned wild-type mice and non-lesioned Cplx2 null mutants. Forced alternation in T-maze, object recognition, social interaction and elevated plus maze tests were unaltered in all groups. The previously reported mild motor phenotype of Cplx2 null mutants was accentuated upon lesion. MRI volumetrical analysis showed a decrease of hippocampal volume exclusively in lesioned Cplx2 null mutants. These findings provide suggestive evidence for the 'second hit' hypothesis of schizophrenia and may offer new tools for the development of advanced treatment strategies.