There are several reports of ultrastructural and protein changes affecting synapses in the anterior cingulate cortex in schizophrenia. Altered cytoarchitecture has also been described in this region in schizophrenia as well as in mood disorders. In this paper we review the literature and present a new study investigating synaptic abnormalities in the anterior cingulate cortex (area 24) in the Stanley Foundation brain series. We used Western blotting to assess four synaptic proteins: synaptophysin, growth-associated protein-43 (GAP-43), complexin I and complexin II, which inform about somewhat different aspects of the synaptic circuitry. Synaptophysin, complexin II and GAP-43 were reduced in bipolar disorder. The decreases correlated with the duration of illness and tended to be greater in subjects without a family history. Complexin II was also reduced in major depression. Complexin I and the housekeeping protein beta-actin did not differ between groups. None of the proteins changed significantly in schizophrenia. The results indicate the presence of a synaptic pathology in the anterior cingulate cortex in mood disorders, especially bipolar disorder. The abnormalities may contribute to the dysfunction of cingulate neural circuits. The loss of synaptophysin is suggestive of decreased synaptic density whilst the decrease in GAP-43 may denote impaired synaptic plasticity and the reduction of complexin II but not complexin I implies that the alterations particularly affect excitatory connections. The reductions may be progressive.