Firings of a Schizophrenic Mind: Faulty neurotransmission and genetics

Schizophrenia is a common neurological disorder which affects 1.0% of the world population and causes a combination of positive (hallucinations, delusions), negative (anhedonia), and cognitive symptoms. Neuropathology is currently explained by genetics and the dopamine, glutamate, and GABA neurotransmitter theories. The dopamine (DA) hypothesis implicates that hyperactive dopaminergic systems lead to schizophrenia, while compromised DA regulation mimics positive symptoms of schizophrenia. The Glutamate and GABA hypotheses explain the negative and cognitive symptoms of schizophrenia left unexplained by the dopamine hypothesis. Mutations in NMDA-receptor subunits, NR1 and NR2A, are main components of regulating glutamate, while the enzyme GAD regulates GABA neurotransmission. Additionally, several genes, including DISC1, DTNBP1, and NRG3, among many possible de novo copy number variant (CNV) mutations, increase susceptibility to schizophrenia. DISC1 regulates mitochondrial function through mitofilin, while NRG3 influences migration and patterning during neurodevelopment through the production of isoforms. The large number of de novo CNV mutations may also contribute to schizophrenia although individual CNV mutations are rare. While interacting neurotransmitter system and genetic alterations can lead to schizophrenia, further evidence is required to understand the interactions of these systems and provide insight into a complex neurological disorder lacking a clear source or pathology.