Schizophrenia is a chronic and severe mental disorder that affects a range of factors in a person, including how he or she thinks, feels, and behaves. Positive symptoms associated with schizophrenia include hallucinations, delusions, movement disorders, and hearing voices, while negative symptoms include reduced expression of emotion, reduced pleasure in everyday life, reduced speaking, and decreased cognitive functioning in many aspects including memory, executive functioning, and maintaining focus. Today roughly 1.2% or 3.2 million Americans are diagnosed with Schizophrenia. Although this mental condition has progressed from previous generations, where the patient was thought to be possessed by evil spirits, many steps toward the underlying causal mechanism have yet to be taken.
Recent studies have shed light onto alterations in Brain Development in patients with schizophrenia. Many studies have shown disruptions in fetal brain development have lead to increased risk in schizophrenia, while other evidence have shown delays in cognitive milestones in early childhood have lead to increased risk in schizophrenia. Altogether, this data suggests brain development has been linked to schizophrenia, and argues that an important factor in disease etiology could be Wnt signaling.
Wnt signaling, a pathway present in many regions of the brain, is important for a number of functions, including neuron plasticity, gene transcription, and overall brain development. In brief, when no Wnt ligand binds to the specific receptor complex, a internal destruction complex exists consisting of glycogen synthase kinase 3 β (GSK3β), Axin, adenomatous polyposis coli (APC), and casein kinase 1 α (CK1α). This complex functions to ultimately phosphorylate an enzyme critical for gene transcription, β-catenin. Overall, this leads to degradation of the enzyme, and a decreased level of gene transcription and neuron development. However in the presence of Wnt signaling (Wnt ligand binds to frizzled receptor complex), an activation of APC an Disheveled (Dvl) occurs, facilitating in the dissociation of the destruction complex, leading to active β-catenin and gene transcription.
Dopamine and Schizophrenia with Wnt signaling
The dopamine signaling pathway is the main target for antipsychotics, well-known drugs that act to reduce psychological effects. Dopamine signaling has a direct relationship with Wnt signaling, overall having a significant impact on (TCF/LEF)-mediated gene transcription. Activating the D2 receptor inhibits the enzyme Akt, which decreases phosphorylation of GSK3β, so overall, Dopamine signaling leads to degraded β-catenin.
Antipsychotic drugs, like clozapine and respiradone, inhibit DA receptors. These studies have established a strong relationship between dopamine signaling, Akt/GSK3β interaction, and Wnt signaling. Overall, the effects of antipsychotic medication act to decrease D2 signaling, and up-regulate Wnt signaling.
All in all, little has been clarified regarding the precise neurological mechanism leading to Schizophrenia. Other than Antipsychotic Drugs, which are accompanied by harsh side effects, treatments for Schizophrenia are therapy-modeled, targeting the patient’s behavioral and thought process. With knowledge of the role of the Wnt signaling pathway in the treatment of Schizophrenia, and other findings within genetics and stem cell research, deeper understanding of the etiology of Schizophrenia is on the horizon, along with how Wnt signaling is being altered to delay brain development.
Schizophrenia and Brain Development
