Disruption of spine homeostasis causes dopaminergic compensatory up-regulation, resulting in schizophrenia.

Schizophrenia is a complex psychiatric disorder clinically categorized into three main symptom domains: positive, negative and cognitive deficits. Many reports have shown that great reduction in spine number was observed in schizophrenia patients. In addition, genetic studies have identified mutations in numerous genes that encode synaptic proteins in schizophrenia patients. Furthermore, it is well known that antipsychotic drugs change the number of spines, indicating that disturbance in spine homeostasis is deeply involved in the pathogenesis of schizophrenia. On the other hand, it is commonly accepted that alteration in dopaminergic systems is also involved in the pathogenesis of schizophrenia. However, the relationships between the changes of spine homeostasis and those of the dopaminergic system are largely unknown. Recently, spine homeostasis is reported to be tightly regulated by dopamine D1 receptors. Thus, I will set a new notion that disturbed spine homeostasis results in compensatory up-regulation in the dopaminergic system to keep normal cognitive functions. The hypothesis is as follows. Disturbance in spine homeostasis based on genetic vulnerabilities is the main cause of schizophrenia, and this disturbance results in network deficiency, negative symptoms and cognitive deficits. Since spine homeostasis is deeply regulated by dopamine D1 receptors, disturbed spine homeostasis leads to compensatory hyperactivity in the dopamine system to keep normal cognitive functions. This dopaminergic hyperactivity stimulates dopamine D2 receptors, leading to positive symptoms. All current antipsychotic medications have antagonist actions at dopamine D2 receptors. However, these drugs are not so effective to negative symptoms, consistent with the hypothesis, where dopamine D2 receptor over-activation is secondary. Thus, this hypothesis can integrally explain three main symptom domains: positive, negative and cognitive deficits.