Dysmodulation of Synapse Formation and Pruning Hypothesis of Schizophrenia

Schizophrenia is a devastating disease that affects at least 1% of humanity. Current understanding is focused on two different hypotheses: excessive dopamine and excessive pruning. Both hypotheses are not totally compliant with observations and are inadequate to provide a unifying framework that explains the cause, mechanism, and symptoms. In this hypothetical work, we propose a unifying hypothesis of schizophrenia. The proposed dysmodulation occurs as a result of growth factor deficiency and any impairment in the related endocrine circuitry. Consequently, synapse formation and pruning processes are regionally and temporally dysmodulated. This dysmodulation results in irregular wiring that contains residual unrelated connections and altered signaling pathways after maturation. We show that available evidence supports the proposed hypothesis, which can explain all the symptoms in a unified framework. If the proposed hypothesis is true, risk group identification and prevention will be straightforward. However, intervention should be performed earlier than currently thought. Unfortunately, after irregular wiring reaches an irreversible steady-state, treatment may not be possible. Nonetheless, even in that case severity of symptoms can be attenuated if the mechanism of synapse formation and pruning is fully understood.