The neuropathological features of
schizophrenia are suggestive of a developmentally induced impairment of synaptic connectivity.
Semaphorin 3A (
sema3A) might contribute to this process because it is a secreted chemorepellant which regulates axonal guidance. We have investigated
sema3A in the cerebellum (an area in which expression persists in adulthood), and measured its abundance in 16 patients with
schizophrenia and 16 controls. In adults,
sema3A was predominantly localized to the inner part of the molecular layer neuropil, whereas infants and rats showed greater labelling of Purkinje cell bodies.
Sema3A was increased in
schizophrenia, as shown by
enzyme-linked
immunosorbent assay (+28%; P<0.05) and immunohistochemistry (+45%; P<0.01). We also measured reelin
mRNA, since reelin is involved in related developmental processes and is decreased in other brain regions in
schizophrenia. Reelin
mRNA showed a trend reduction in the subjects with
schizophrenia (-26%; P=0.07) and, notably, was negatively correlated with
sema3A.
Sema3A also correlated negatively with
synaptophysin and
complexin II mRNAs. The results show that
sema3A is elevated in
schizophrenia, and is associated with downregulation of genes involved in synaptic formation and maintenance. In this respect,
sema3A appears to contribute to the synaptic pathology of
schizophrenia, perhaps via ongoing effects of persistent
sema3A elevation on synaptic plasticity. The findings are consistent with an early neurodevelopmental origin for the disorder, and the reciprocal changes in
sema3A and reelin may be indicative of a pathogenic mechanism that affects the balance between trophic and inhibitory factors regulating synaptogenesis.