The impact of Disrupted-in-Schizophrenia 1 (DISC1) on the dopaminergic system: a systematic review

Although the Disrupted-in-Schizophrenia 1 (DISC1) was found as a risk gene that may account for mental symptoms of a specific pedigree in the past, it is now known as a risk biological factor for mental illnesses possibly associated with dopamine impairments. DISC1 is a scaffold protein interacting with proteins involved in the dopamine system. Here, we summarize the impact of DISC1 disruption on the dopamine system in animal models, considering its effects on presynaptic dopaminergic function (tyrosine hydroxylase levels, dopamine transporter levels, dopamine levels at baseline and after amphetamine administration), and post-synaptic dopaminergic function (dopamine D1 and D2 receptor levels, dopamine receptor binding potential, and locomotor activity after amphetamine administration). Our findings show that many, but not all DISC1 models display 1) increased locomotion after amphetamine administration 2) increased dopamine levels after amphetamine administration in the nucleus accumbens 3) inconsistent basal dopamine levels, dopamine receptor levels and binding potentials. There is also limited evidence for decreased tyrosine hydroxylase levels in the frontal cortex and increased dopamine transporter levels in the striatum but not nucleus accumbens, but these conclusions warrant further replication. The main dopaminergic findings are seen across different DISC1 models, providing convergent evidence that DISC1 has a role in regulating dopaminergic function. These results implicate dopaminergic dysregulation as a mechanism underlying the increased rate of schizophrenia seen in DISC1 variant carriers, and provide insights into how Disc1, and potentially DISC1-interacting proteins such as Akt and GSK-3, could be used as novel therapeutic targets for schizophrenia