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Emerging Biological and Molecular Targets in Schizophrenia
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Emerging Biological and Molecular Targets in Schizophrenia

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: 25 December 2026 | Viewed by 13687

Special Issue Editor

Dr. Jacopo Sapienza

E-Mail Website
Guest Editor
1. Department of Clinical Neurosciences, IRCCS San Raffaele, Milan, Italy
2. Department of Humanities and Life Sciences, University School for Advanced Studies IUSS, Pavia, Italy
Interests: schizophrenia; psychedelics; psychopharmacology; clozapine; kynurenine pathway; inflammation; cognition; language

Special Issue Information

Dear Colleagues,

Schizophrenia is characterized by several symptom dimensions that show high heterogeneity in terms of biological underpinnings. Licensed pharmacological treatments can manage positive symptoms quite well, although not always satisfactorily. However, negative and cognitive symptoms still represent unmet clinical needs only partially addressed by drugs and rehabilitations strategies. Thus, the identification of new targets of treatment is of paramount importance to ameliorate daily functioning and quality of life for people with schizophrenia. Mounting evidence points to a multitude of new potential biological/molecular targets for pharmacological and non-pharmacological treatments that go beyond the conventional dopaminergic system. Modulation of NMDARs and other receptors (cholinergic, GABA), neuroplasticity, and synaptic homeostasis, as well as Trace Amine-Associated Receptors (TAARs), the kynurenine pathway—regarding, in particular, kynurenic acid (KYNA), and neuroinflammation are just some of the candidate systems. Some preclinical evidence, combined with old clinical studies, also lays the foundation for starting to consider psychedelics as a possible treatment for deficit-schizophrenia. In conclusion, all papers with the aim of disentangling possible determinants of illness and/or identifying new possible targets for pharmacological and non-pharmacological interventions for schizophrenia are welcome. Opinion papers and perspectives with a strong scientific rationale are welcome as well.

Dr. Jacopo Sapienza
Guest Editor

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Keywords

  • schizophrenia
  • cognition
  • negative symptoms
  • synapses
  • kynurenine pathway
  • TAAR1
  • psychedelics
  • new treatments

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Published Papers (4 papers)

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Research

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11 pages, 239 KB  
Communication
Positive and Negative Symptoms of Schizophrenia and Polymorphic Variants of the TCF4 Gene: Pilot Associative Study
by Svetlana A. Ivanova, Vladimir V. Tiguntsev, Anastasia S. Boiko, Ekaterina V. Mikhalitskaya, Dmitry A. Petkun, Irina A. Mednova, Olga Yu. Fedorenko, Nikolay A. Skryabin, Elena G. Kornetova, Alexander N. Kornetov and Nikolay A. Bokhan
Int. J. Mol. Sci. 2025, 26(21), 10507; https://doi.org/10.3390/ijms262110507 - 29 Oct 2025
Cited by 1 | Viewed by 1112
Abstract
The role of the genetic component in the development of schizophrenia and the formation of its clinical heterogeneity has been proven. To conduct a pilot associative analysis between positive and negative schizophrenia symptoms and polymorphic variants of the Transcription Factor 4 (TCF4 [...] Read more.
The role of the genetic component in the development of schizophrenia and the formation of its clinical heterogeneity has been proven. To conduct a pilot associative analysis between positive and negative schizophrenia symptoms and polymorphic variants of the Transcription Factor 4 (TCF4) gene. The study included 373 patients with schizophrenia of Caucasian ethnicity, who underwent a comprehensive clinical examination, and a control group consisted of 194 mentally and somatically healthy individuals. Genotyping of three polymorphic variants of the TCF4 gene was carried out in the studied samples (rs2958182, rs8766, and rs9636107). Statistical analysis of the results was performed using Statistica for Windows V.12.0. Association analysis in SNPs was conducted using the chi-square criterion and Bonferroni correction. Groups of schizophrenia patients and healthy individuals were compared for selected TCF4 gene polymorphisms. No statistically significant differences in genotype and allele frequencies were found. The AA genotype and the A allele of the rs2958182 polymorphic variant, as well as the A allele of the rs9636107 polymorphic variant, had an effect predisposing to the predominance of negative symptoms. The TT genotype and the T allele of the rs2958182 polymorphic variant, as well as the G allele of the rs9636107 polymorphic variant, were statistically significantly more common among patients with leading positive symptoms. As a result of the study, associations of the polymorphic variant TCF4 rs2958182 and TCF4 rs9636107 with the leading symptoms of schizophrenia were discovered for the first time in Caucasian populations of the Siberian region. The obtained data confirm the contribution of the genetic component to the formation of clinical heterogeneity of schizophrenia and open up prospects for further search for genetic markers in order to prevent an unfavorable outcome of the disease. Full article
(This article belongs to the Special Issue Emerging Biological and Molecular Targets in Schizophrenia)
12 pages, 2948 KB  
Article
Molecular Mimicry Between Toxoplasma gondii B-Cell Epitopes and Human Antigens Related to Schizophrenia: An In Silico Approach
by Juan F. Cano, Maria Andrea Bernal-Valencia, Pablo Vargas-Acevedo, Germán Mejía-Salgado, Andrés Sánchez, Oscar Correa-Jiménez, Marlon Múnera and Alejandra de-la-Torre
Int. J. Mol. Sci. 2025, 26(21), 10321; https://doi.org/10.3390/ijms262110321 - 23 Oct 2025
Viewed by 1190
Abstract
Schizophrenia is a complex disorder influenced by genetic, neurobiological, and environmental factors, with increasing evidence implicating immune dysregulation. This study examined potential molecular mimicry between autoantigens associated with schizophrenia and proteins from Toxoplasma gondii, a parasite previously linked to the disorder. Amino [...] Read more.
Schizophrenia is a complex disorder influenced by genetic, neurobiological, and environmental factors, with increasing evidence implicating immune dysregulation. This study examined potential molecular mimicry between autoantigens associated with schizophrenia and proteins from Toxoplasma gondii, a parasite previously linked to the disorder. Amino acid sequences of schizophrenia-related autoantigens were retrieved from databases (AAgAtlas, PubMed), and homologous sequences were searched within the T. gondii proteome. Sequence identity was evaluated, and conserved B-cell epitopes were predicted using three-dimensional structures from the Protein Data Bank or models generated in Swiss-Model, followed by epitope mapping with ElliPro. Five autoantigens—gamma-enolase (ENO2), thyroid peroxidase (TPO), glutamic acid decarboxylase 65 kDa isoform (GAD65), serine/threonine-protein kinase 2 (VRK2), and dihydropyrimidine dehydrogenase [NADP(+)] (DPYD)—showed similarities with T. gondii proteins. Among them, enolase exhibited the highest homology, with identities up to 65%. These findings provide preliminary evidence of shared antigenic features between the parasite and schizophrenia-related autoantigens. Such mimicry could contribute to disease mechanisms by triggering autoimmune responses in genetically susceptible individuals, supporting the hypothesis that T. gondii infection may influence schizophrenia pathogenesis. Nonetheless, the results are based exclusively on in silico analyses, and experimental validation will be required to confirm potential cross-reactivity. Full article
(This article belongs to the Special Issue Emerging Biological and Molecular Targets in Schizophrenia)
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Other

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15 pages, 498 KB  
Perspective
Microdosing Psychedelics to Restore Synaptic Density in Schizophrenia
by Jacopo Sapienza, Marco Spangaro, Stefano Comai, Michel Sabé, Joseph La Torre, Matteo Buonarroti, Roberto Cavallaro and Marta Bosia
Int. J. Mol. Sci. 2025, 26(18), 8949; https://doi.org/10.3390/ijms26188949 - 14 Sep 2025
Cited by 2 | Viewed by 8741
Abstract
Schizophrenia is a highly polygenic disease, and several genetic variants associated with the disease converge on altered synaptic homeostasis. In particular, the gene encoding complement component 4 (C4) showed the strongest association with schizophrenia, and this protein is involved in complement-dependent and microglia-mediated [...] Read more.
Schizophrenia is a highly polygenic disease, and several genetic variants associated with the disease converge on altered synaptic homeostasis. In particular, the gene encoding complement component 4 (C4) showed the strongest association with schizophrenia, and this protein is involved in complement-dependent and microglia-mediated synaptic pruning. As a matter of fact, microglia are overactive in schizophrenia, and reduced synaptic arborization, especially in the prefrontal cortex (PFC), is an established hallmark of schizophrenia, likely associated with gray matter loss, cortical thinning, hypofrontality, and deficit syndrome. The recent development of a new radioligand targeting the synaptic vesicle glycoprotein 2A (SV2A) demonstrated in vivo lower synaptic density at the PFC level in individuals with schizophrenia, corroborating the synaptic hypothesis of thedisease first proposed by Feinberg in 1982. Interestingly, robust preclinical evidence (in vitro and animal models) showed the ability of psychedelics to promote neuroplasticity and synaptogenesis, potentially counteracting the excessive synaptic loss, restoring volume loss, and possibly explaining improvements in negative and cognitive symptoms described by old clinical studies. Overall, microdoses should be explored first as a possible treatment in a selected sample of patients affected by deficit schizophrenia, followed by low and full doses if encouraging results were to emerge. Full article
(This article belongs to the Special Issue Emerging Biological and Molecular Targets in Schizophrenia)
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13 pages, 692 KB  
Brief Report
Differential Association of the DISC1 Interactome in Hallucinations and Delusions
by Araceli Gutiérrez-Rodríguez, Alma Delia Genis-Mendoza, Jorge Ameth Villatoro-Velázquez, María Elena Medina-Mora and Humberto Nicolini
Int. J. Mol. Sci. 2025, 26(17), 8738; https://doi.org/10.3390/ijms26178738 - 8 Sep 2025
Cited by 1 | Viewed by 1698
Abstract
Multiple genes within the DISC1 (Disrupted-in-Schizophrenia-1) interactome have been implicated in psychotic disorders, which are characterized by hallucinations, delusions, negative symptoms, and disorganized behavior. However, the genetic associations of specific psychotic symptoms remain poorly understood. Methods: We conducted a genetic association analysis of [...] Read more.
Multiple genes within the DISC1 (Disrupted-in-Schizophrenia-1) interactome have been implicated in psychotic disorders, which are characterized by hallucinations, delusions, negative symptoms, and disorganized behavior. However, the genetic associations of specific psychotic symptoms remain poorly understood. Methods: We conducted a genetic association analysis of the DISC1 interactome for hallucinations and delusions in schizophrenia and bipolar disorder, using single-nucleotide polymorphism (SNP), gene, and gene-set approaches. Results: Our findings showed an association between the SNP rs6754640 in the NRXN1 gene and auditory hallucinations. Additionally, rs10263196 (EXOC4), rs7076156 (ZNF365), and nine NRXN1 SNPs were associated with delusions of reference, while rs17039676 (NRXN1) was linked to persecutory delusions. At the gene level, NRG1 and PCM1 were related to auditory hallucinations. The NRXN1, APP, EXOC4, and NUP210 genes were associated with delusions of reference, whereas NRG1 and APP were linked to persecutory delusions. Gene-set analysis indicated that pathways related to the regulation of neuronal structure and function were involved in auditory hallucinations, while cellular transport regulation pathways were associated with persecutory delusions. Conclusions: This study emphasizes the polygenic architecture of psychosis and suggests that distinct molecular mechanisms contribute to different types of hallucinations and delusions. Full article
(This article belongs to the Special Issue Emerging Biological and Molecular Targets in Schizophrenia)
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