ABSTRACT
Disrupted-in-Schizophrenia 1 (DISC1) is a gene known as a risk factor for mental illnesses possibly associated with dopamine impairments. DISC1 is a scaffold protein interacting with proteins involved in the dopamine system. Here we summarise 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 postsynaptic 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, and (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.
Subject(s)
Locomotion/genetics , Nerve Tissue Proteins/genetics , Amphetamine/pharmacology , Animals , Dopamine/metabolism , Dopamine Plasma Membrane Transport Proteins/metabolism , Dopamine Uptake Inhibitors/pharmacology , Locomotion/drug effects , Mice , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , Rats , Receptors, Dopamine D1/metabolism , Receptors, Dopamine D2/metabolism , Tyrosine 3-Monooxygenase/metabolismSubject(s)
Dopamine/pharmacology , Nerve Tissue Proteins/drug effects , Nerve Tissue Proteins/metabolism , Protein Aggregates/drug effects , Cell Line, Tumor , Humans , Microscopy, Immunoelectron , Mitochondria/drug effects , Nerve Tissue Proteins/ultrastructure , Neuroblastoma/metabolism , Neuroblastoma/pathology , Neuroblastoma/ultrastructure , Protein Transport/drug effects , Vimentin/metabolismABSTRACT
Disrupted-in-schizophrenia 1 (DISC1) is a mental illness gene first identified in a Scottish pedigree. So far, DISC1-dependent phenotypes in animal models have been confined to expressing mutant DISC1. Here we investigated how pathology of full-length DISC1 protein could be a major mechanism in sporadic mental illness. We demonstrate that a novel transgenic rat model, modestly overexpressing the full-length DISC1 transgene, showed phenotypes consistent with a significant role of DISC1 misassembly in mental illness. The tgDISC1 rat displayed mainly perinuclear DISC1 aggregates in neurons. Furthermore, the tgDISC1 rat showed a robust signature of behavioral phenotypes that includes amphetamine supersensitivity, hyperexploratory behavior and rotarod deficits, all pointing to changes in dopamine (DA) neurotransmission. To understand the etiology of the behavioral deficits, we undertook a series of molecular studies in the dorsal striatum of tgDISC1 rats. We observed an 80% increase in high-affinity DA D2 receptors, an increased translocation of the dopamine transporter to the plasma membrane and a corresponding increase in DA inflow as observed by cyclic voltammetry. A reciprocal relationship between DISC1 protein assembly and DA homeostasis was corroborated by in vitro studies. Elevated cytosolic dopamine caused an increase in DISC1 multimerization, insolubility and complexing with the dopamine transporter, suggesting a physiological mechanism linking DISC1 assembly and dopamine homeostasis. DISC1 protein pathology and its interaction with dopamine homeostasis is a novel cellular mechanism that is relevant for behavioral control and may have a role in mental illness.
Subject(s)
Dopamine/metabolism , Nerve Tissue Proteins/metabolism , Amphetamine , Animals , Behavior, Animal/physiology , Brain/metabolism , Disease Models, Animal , Dopamine Plasma Membrane Transport Proteins/genetics , Homeostasis/physiology , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Nerve Tissue Proteins/genetics , Neurons/metabolism , Rats , Rats, Sprague-Dawley , Rats, Transgenic , Receptors, Dopamine D2/metabolism , Schizophrenia/genetics , Synaptic TransmissionABSTRACT
Following oral or IV administration, dopamine (DA) cannot cross the blood-brain barrier to a significant extent, but can enter the brain when administered via the nasal passages. Intranasal administration of DA was shown to increase extracellular DA in the striatum, to have antidepressant action and to improve attention and working memory in rats. Here we show that aged (22-24 months old) rats are deficient in an object-place learning task, but that this learning/memory is intact and comparable with that of adult rats upon pre-trial administration of 0.3 mg/kg DA gel into the nasal passages. This result raises the possibility of the therapeutic application of intranasal DA treatment for age-related cognitive disorders.
