Neurodevelopmental, neurochemical, and environmental contributions to SZ pathogenesis.
| Variable | Impacts on SZ |
|---|---|
| Developmental factor | |
| Prenatal insults (hypoxia, maternal infections) | Increases risk by altering neurodevelopmental pathways |
| Synaptic pruning abnormalities | Leads to disrupted neuronal connectivity and increased vulnerability to psychosis |
| Structural brain abnormalities | Enlarged ventricles, changes in the frontal and temporal lobes |
| C4A locus in the MHC region | Implicated in excessive synaptic pruning |
| Copy number variations (CNVs) | Linked to SZ and developmental disorders |
| Induced pluripotent stem cell (iPSC) models | Demonstrate how NRXN1 deletions disrupt synaptic function |
| Neurochemical dysregulation factor | |
| Glutamate (NMDA receptor dysfunction) | Leads to excitotoxicity and cognitive impairments |
| GABAergic dysfunction | Disrupts the excitatory-inhibitory balance |
| Dopamine (mesolimbic and mesocortical pathways) | Excess in the mesolimbic system (positive symptoms), deficit in the mesocortical system (negative symptoms) |
| Kynurenine pathway | Increased kynurenic acid disrupts glutamate and dopamine neurotransmission |
| Cytokine-mediated neuroinflammation | Elevated IL-6, TNF-α, and IFN-γ contribute to neurotransmitter dysregulation |
| Environmental risk factors | |
| Prenatal maternal infection (influenza, CMV, rubella, Toxoplasma gondii) | Triggers immune activation leading to neurodevelopmental disruption |
| Obstetric complications (hypoxia, preeclampsia, emergency C-section) | Increases SZ risk by impairing brain development |
| Maternal stress & malnutrition | Affects fetal brain development and neurotransmitter synthesis |
| Early-life adversity (childhood trauma, abuse, neglect) | Linked to increased risk of SZ and substance use disorder |
| Gut dysbiosis & microbiota alterations | Affects neurotransmitter balance and neuroinflammation |
C4A: component 4A; GABA: gamma-aminobutyric acid; IFN-γ: interferon-gamma; IL-6: interleukin-6; MHC: major histocompatibility complex; NMDA: N-methyl-D-aspartate; NRXN1: neurexin 1; SZ: schizophrenia; TNF-α: tumor necrosis factor-alpha.
TAO: Conceptualization, Investigation. OJO: Conceptualization, Data curation, Investigation, Writing—original draft, Writing—review & editing. UOA: Conceptualization, Data curation, Investigation, Writing—original draft, Writing—review & editing. KBO: Conceptualization, Data curation, Investigation, Writing—original draft. SSM: Conceptualization, Data curation, Investigation, Writing—original draft, Writing—review & editing. MMA: Conceptualization, Data curation, Investigation, Writing—original draft, Writing—review & editing. AKA: Conceptualization, Data curation, Investigation, Writing—original draft, Writing—review & editing. ABO: Writing—original draft. JOO: Writing—original draft, Writing—review & editing. GE: Writing—review & editing. DELP: Writing—review & editing, Supervision. All authors have read and approved the submitted version.
The authors declare that they have no conflicts of interest.
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