Investigation of Tight Junction Protein Alterations in ADHD: The Role of Claudin-5,β-Catenin and Paxillin

Abstract

Objective:

Blood-brain barrier permeability (BBB) has been suggested to be involved in the etiopathogenesis of ADHD. Claudin-5, β-catenin and paxillin are important molecules with different roles in this barrier. Alterations in these molecules may disrupt the neurodevelopmental process by affecting various critical processes in the developing brain. Therefore, this study aimed to evaluate whether the peripheral levels of these molecules differ in children and adolescents with ADHD.

Method:

A total of 90 patients with ADHD aged between 8 and 18 years and 60 healthy controls were included in this study. The severity of ADHD symptoms was determined with the Atilla Turgay Scale. Child Anxiety-Depression Scale-Revised was completed to evaluate additional psychiatric problems of the patients. Serum levels of biochemical parameters were measured using enzyme-linked immunosorbent assay kits.

Results:

Serum claudin-5 levels were significantly lower and β-catenin levels were significantly higher in the ADHD group compared to the control group. However, there was no significant difference in paxillin serum levels between the groups.

Conclusion:

This study suggests that claudin-5 and beta-catenin may play a role in the pathogenesis of ADHD. These proteins may affect the brain by causing a dysregulation in BBB permeability or through other mechanisms.

Keywords

ADHD beta-catenin blood-brain barrier claudin-5 paxillin

Introduction

ADHD is a neurodevelopmental disorder that usually initiates in childhood and may continue in adulthood, characterized by inattention, hyperactivity/impulsivity and impairs the functionality of the individual (Thapar & Cooper, 2016). ADHD is a common reason for outpatient clinic visits in childhood and adolescence (Türkoğlu, 2014). It has been reported that the prevalence of ADHD varies between 2% and 7% worldwide with an average of 5% (Polanczyk et al., 2015). Although ADHD is a common disorder, its etiology has not been fully elucidated although genetic, neurobiological and environmental factors are thought to be effective in its etiopathogenesis (Thapar & Cooper, 2016). It is thought that changes in the blood brain barrier (BBB) structure, which have attracted increasing attention in the etiology of psychiatric disorders including schizophrenia, major depressive disorder and bipolar disorder in recent years, may also be effective in the etiopathogenesis of ADHD (Aydoğan Avşar et al., 2020; Najjar et al., 2017). However, data on the relationship between alterations in the structure of the BBB and ADHD are limited in the literature.

The BBB is a structure that prevents the transfer of harmful molecules from the peripheral circulation to the brain and sometimes regulates homeostasis by allowing the transfer of some molecules (Greene et al., 2020). Recent studies seriously point out that there is a relationship between structural changes in the BBB and psychiatric disorders. A recent study has shown that patients with bipolar disorder and schizophrenia have alterations in claudin and metallopeptidase-1 molecules indicating disruptions in the structure of the BBB (Lizano et al., 2023). In autism spectrum disorder (ASD), which is one of the other common neurodevelopmental disorders, there are data showing disruptions in the BBB structure such as neuron-specific enolase and creatine kinase brain isoenzyme changes (Lv et al., 2016). In addition to these data, recent studies suggest that BBB alterations are also observed in ADHD (Aydoğan Avşar et al., 2020; Ferahkaya et al., 2024).

Tight junctions (TJs) form the basis of all barrier systems including the BBB. TJs are dynamic structures formed by configurations of different proteins. The claudin family is one of the main proteins that form TJs. Claudin-5 is a member of this family and has an important role in the regulation of paracellular ionic permeability and is the most common isoform in the BBB. In a recent study, it was found that the levels of claudin-5 were significantly decreased in the hippocampus grey matter of individuals diagnosed with depression and schizophrenia (Greene et al., 2020). In addition to this study, it has been reported that claudin-5 changes could be involved in mechanisms underlying psychiatric disorders including schizophrenia, obsessive-compulsive disorder (OCD) and bipolar disorder (BPD; Greene et al., 2018; Işık et al., 2021; Kılıç et al., 2020). There are only two studies in the literature investigating claudin-5 levels in ADHD sample and although the results of these studies contradict each other, both studies indicate that there may be structural changes in the BBB in ADHD (Aydoğan Avşar et al., 2020; Ferahkaya et al., 2024).

β-catenin is a subunit of the cadherin protein complex and is also an important component of the WNT signaling pathway. In addition to its functions including cell adhesion and gene transcription, it induces endothelial barrier functions and plays an important role in ensuring barrier continuity (MacDonald et al., 2019). Studies indicate that the WNT/β-catenin pathway may play a role in the etiopathogenesis of psychiatric disorders (Santos et al., 2021; Zhang & Li, 2021). In a recent study, increased β-catenin levels were found in ASD (Bilgic et al., 2023). It is thought that the WNT/β-catenin pathway may be involved in the etiology of ADHD at genetic, environmental and pharmacotherapeutic levels (Yde Ohki et al., 2020). There is no study in the literature investigating the relationship between β-catenin levels in the peripheral circulation and ADHD.

Paxillin is a member of the group III LIM domain protein family that binds the integrin-mediated signal to the actin cytoskeleton, which has a very important role in cell adhesion (Ma & Hammes, 2018). In addition to its role in cell adhesion, it plays an important role in the regulation of cell proliferation, migration and dynamic changes required for cell survival in these processes and in cytoskeletal reorganization (Deakin & Turner, 2008). In the light of this information, paxillin may play a role in the etiopathogenesis of ADHD by affecting developmental processes in addition to its possible roles in the formation and maintenance of barrier structures. There is no study in the literature investigating the relationship between serum paxillin levels and ADHD.

Although it is thought that structural changes in the BBB and some proteins involved in the BBB may play a role in the etiopathogenesis of ADHD with this information in the literature, the available information is quite limited. Therefore, evaluation of claudin-5, β-catenin and paxillin levels in children with ADHD may be valuable in terms of clarifying the etiopathogenesis of the disorder. We planned this study based on the hypotheses that these molecules would differ in children with ADHD compared to healthy controls and could be involved in mechanisms underlying ADHD severity.

Methods

Sample

The patient group of our study was consisted of children and adolescents aged between 8 and 18 years who applied to a child and adolescent psychiatry outpatient clinic and who were diagnosed with ADHD according to Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5; American Psychiatric Association, 2013). The control group was consisted of healthy children who applied to a pediatric outpatient clinic for routine follow-up and controls. The exclusion criteria for both groups were chronic respiratory, physical, metabolic, genetic, neurological and endocrinological diseases and psychotropic drug use in the last six months. In addition, a diagnosis of any psychiatric disorder was determined as an exclusion criterion for the control group.

Our study included 90 participants with ADHD and 60 healthy controls. Based on an independent two-sample t-test, this sample size provides approximately 80% power to detect a medium effect size of Cohen’s d ≈ .47 at a significance level of α = .05. Given the exploratory nature of our investigation and limited prior data on BBB-related biomarkers in ADHD, this sample size is reasonable to identify moderate group differences. Nonetheless, larger samples will be necessary in future studies to confirm and extend these findings.

All research procedures were conducted in accordance with the Declaration of Helsinki and local laws and regulations. Approval for this study was obtained from Ethics Committee of local university. Verbal and informed written consent was obtained from the parents of all participants.

Diagnosis and Symptom Assessment

The diagnosis of ADHD was made on the basis of DSM-5 criteria with the patient’s history and psychiatric examination using the Schedule for Affective Disorders and Schizophrenia for School-Aged Children, Present and Lifetime Version (K-SADS-PL; American Psychiatric Association, 2013; Kaufman et al., 1997; Ünal et al., 2019). Symptom severity of the patients was determined by Atilla Turgay DSM-IV-Based Screening Scale for Disruptive Behavior Disorders in Children and Adolescents (T-DSM-IV-S). In addition, in order to evaluate the additional psychiatric problems of the patients, the Revised Child Anxiety Depression Scale Child Form (RCADS-CF) version was administered to the patients. The subjects included in the control group were evaluated with the same procedures as the patient group and completed the scale forms. Body mass indexes (BMI) of both groups were calculated and recorded. T-DSM-IV-S is a scale developed by Atilla Turgay which questions inattention, hyperactivity, impulsivity, oppositional defiant disorder and conduct disorder (Ercan et al., 2001). RCADS-CF was developed to screen anxiety disorders and depression in children and adolescents. Turkish validity and reliability study was conducted by Görmez et al. (Gormez et al., 2017).

Blood Samples

Venous blood samples of the participants in the patient and control groups were taken from the antecubital vein in the morning of the psychiatric evaluation in plastic tubes with K3EDTA. The 5 mL venous blood sample was centrifuged at 4°C, 4,000 rpm for 10 min and the serum samples were stored at −80°C until the date of biochemical analyses. Serum levels of claudin-5 (Cloud Clone (USCN)), β-catenin (Cloud Clone (USCN)) and paxillin (Nephente) were measured by double antibody sandwich enzyme-linked immunosorbent assay (ELISA) according to the manufacturer’s instructions. All biochemical parameter results were calculated as ‘ng/mL’ according to absorbance-concentration calibration graphs

Statistical Analysis

SPSS 21.0 was used for statistical analyses in our study. Independent sample t-test was used for two-group comparison for normally distributed parameters, and Mann-Whitney U test was used for two-group comparison for non-normally distributed data. In addition, a multivariate analysis of covariance (MANCOVA) was performed to reduce the risk of type I errors related to the multiple-test effect and to control for potential confounding factors such as age, gender and BMI. After determining that there was a significant difference between the study and control groups by performing MANCOVA, a one-way analysis of covariance (ANCOVA) was performed on the outcome variables. Non-normally distributed variables were log-transformed and log-transformed values were used in MANCOVA and ANCOVA. Pearson chi-square analysis was used to compare categorical parameters. Pearson or Spearman correlation analyses were used for correlation of quantitative parameters. In our study, Type-1 error (α) value .05 (5%) and p significance level <.05 were accepted

Results

A total of 90 children and adolescents (64 boys and 26 girls) diagnosed with ADHD constituted the patient group and 60 healthy children and adolescents (39 boys and 21 girls) constituted the control group. The mean age of the patient group was 11.32 ± 2.79 years and the mean age of the control group was 11.95 ± 2.77 years. No significant difference was found between the groups in terms of sex distribution and age. BMI of the patient group was calculated as 19.6 ± 3.8 and BMI of the control group was calculated as 19.9 ± 4.6 and no statistically significant difference was found between the groups. Demographic data of the ADHD and control groups are given in Table 1. The total and all subscale scores of the T-DSM-IV-S were significantly higher in the ADHD group compared to the control group, whereas no statistically significant difference was found between the groups in the R-CADS scale score.

Table 1.

Demographic Characteristics of ADHD and Controls and Scale Scores of ADHD Group.

Variables	ADHD (n = 90)		Controls (n = 60)		Statistical analysis
Variables	n	%	n	%	x ²	p	Cohen’s d
Gender (boy/girl)	64/26	71.1/28.9	39/21	65/35	0.625	.429
	Mean	SD	Mean	SD	t	p
Age (years)	11.32	2.79	11.95	2.77	−1.352	.178	0.226
BMI	19.67	3.82	19.92	4.61	−0.354	.724	0.059

Note. BMI = Body Mass Index; SD = standard deviation.

In the analyses, claudin-5 levels were statistically significantly lower and β-catenin levels were statistically significantly higher in the patient group compared to the control group. However, no significant difference was found between the groups in terms of paxillin levels. The MANCOVA test demonstrated that there were significant differences between the groups for the whole sample (Pillai’s Trace V= 0.084, F = 4.315, p = .006 and η_p² = .084). Separate univariate ANCOVAs were used after being adjusted confounding factors. After controlling for age, gender and BMI, the statistically significant differences in claudin-5 and β-catenin levels between the groups remained, whereas no significant difference was found in paxillin levels. The results of biochemical parameter levels and analyses are given in Table 2.

Table 2.

Serum Claudin-5, β-catenin and Paxillin Levels of ADHD and Controls.

	ADHD (n = 57)	Controls (n = 60)	Statistical analysis
					ANCOVA^b
	Mean ± SD	Mean ± SD	z/t	p	F	p	η_p ²
Claudin-5^c (ng/mL)	9.43 ± 8.34	11.91 ± 9.19	−2.555	.011^a	7.052	.009	0.047
β-catenin^c (ng/mL)	22.28 ± 30.25	13.26 ± 11.04	−2.035	.042^a	4.807	.030	0.033
Paxillin^c (ng/mL)	9.64 ± 5.07	9.59 ± 6.04	−0.476	.634^a	0.166	.685	0.001

Note. SD = standard deviation.

Mann-Whitney U test.

Analysis of covariance (ANCOVA) analyses adjusting for age, sex and body mass index for comparisons.

Serum claudin-5, β-catenin and paxillin levels were log-transformed prior to ANCOVA analysis.

In the correlation analyses, no statistically significant correlation was found between the serum levels of biochemical parameters and T-DSM-IV-S and RCADS-CF scores.

Discussion

In this study, we investigated whether serum levels of claudin-5, β-catenin and paxillin are could be involved in mechanisms underlying ADHD in childhood and adolescence. We found that serum levels of claudin-5 were statistically significantly lower and β-catenin were statistically significantly higher in children with ADHD compared to healthy controls, and these significant differences persisted after controlling for confounding factors. However, we found no significant difference in serum paxillin levels between ADHD and control groups.

Claudin-5 is an important component of TJs in the BBB. TJs prevent the passage of pathogenic molecules to the central nervous system and the brain is more exposed to adverse environmental factors in claudin-5 dysfunction (Omidinia et al., 2014). The number of studies investigating the relationship between claudin-5 and psychiatric disorders in the literature is not sufficient to elucidate this complex relationship. In a recent study, Green et al. demonstrated that claudin-5 levels decreased in schizophrenia and depression (Greene et al., 2020). In two studies conducted with patients diagnosed with schizophrenia, decreased levels of claudin-5 were found and it was reported that this decrease disrupted the BBB structure and made the brain more sensitive to environmental factors, which may be effective in the development process of schizophrenia (Maes et al., 2019; Usta et al., 2021). In a recent study, an increase in the level of claudin-5 was found in individuals diagnosed with specific learning disorder, which is a neurodevelopmental disorder like ADHD, and it was stated that this may indicate impairment in the integrity of the BBB (Tanir et al., 2023). There are studies reporting that changes in claudin-5 levels in peripheral circulation are observed in ASD, another important neurodevelopmental disorder (Bilgic et al., 2023; McCullumsmith et al., 2007). To the best of our knowledge, only two studies, including the previous study of one of our team, have examined the relationship between ADHD and claudin-5 (Aydoğan Avşar et al., 2020; Ferahkaya et al., 2024). Aydogan et al. found increased claudin-5 levels in the group diagnosed with ADHD and interpreted the change as a compensatory increase secondary to BBB deterioration (Aydoğan Avşar et al., 2020). In our previous study, we found decreased claudin-5 levels in patients with ADHD compared to healthy controls, consistent with the results of the present study (Ferahkaya et al., 2024).

We found that β-catenin levels were increased in the ADHD group, and our study is the first to investigate the relationship between ADHD and β-catenin. β-catenin is a multifunctional protein, playing a central role in the Wnt signaling pathway and cell adhesion (MacDonald et al., 2019), as well as in processes such as cell proliferation, immune regulation and development (Chandrakesan et al., 2013). Therefore, alterations in β-catenin levels in serum may originate from both central and peripheral mechanisms. In the literature, associations between β-catenin and several psychiatric disorders have been reported. For example, increased β-catenin levels and activation of the Wnt/β-catenin pathway have been observed in individuals with ASD (Bilgic et al., 2023; Caracci et al., 2016), whereas decreased β-catenin protein and mRNA expression in the dorsolateral prefrontal cortex and temporal cortex have been reported in postmortem studies of bipolar disorder patients compared to healthy controls (Pandey et al., 2015). The prefrontal cortex is one of the most important anatomical regions implicated in ADHD, and alterations in β-catenin protein or mRNA expression in this area may contribute to the etiopathogenesis of the disorder. Further evidence for the potential involvement of the Wnt/β-catenin pathway in ADHD comes from experimental studies (Abu-Elfotuh et al., 2022; Custodio et al., 2023). For instance in a rat model of ADHD induced by monosodium glutamate, treatment with monosodium glutamate antagonists appeared to act, at least in part, through β-catenin–related mechanisms (Abu-Elfotuh et al., 2022). Based on these data, the elevated β-catenin levels in our ADHD group may reflect compensatory regulation in processes involving this protein. While these findings are consistent with the possible involvement of BBB-related molecular pathways, they should be interpreted cautiously given the multiple roles of β-catenin and the potential contribution of peripheral sources.

Previous studies have reported differing directions of change in claudin-5 and β-catenin levels across neuropsychiatric disorders. For example, Aydogan et al. observed elevated claudin-5 in children with ADHD, whereas we detected reduced levels in our sample (Aydoğan Avşar et al., 2020). In addition, we observed elevated β-catenin levels in individuals with ADHD. In contrast, postmortem brain studies have reported reduced β-catenin levels in the dorsolateral prefrontal and temporal cortices of individuals with bipolar disorder, while no significant alterations were detected in schizophrenia. Nonetheless, evidence suggests that dysregulation of the Wnt/β-catenin pathway may contribute to the pathophysiology of schizophrenia (Pandey et al., 2015; Vallée, 2022). These discrepancies may stem from methodological differences (e.g., plasma vs. serum measurements, assay sensitivity and sample handling), variations in participant characteristics (age, developmental stage, medication exposure and comorbidities) and the influence of acute stress or systemic inflammation on protein expression. Furthermore, claudin-5 and β-catenin regulation is highly context-dependent; changes may reflect compensatory upregulation in some conditions and downregulation in others, even within related neurodevelopmental or psychiatric phenotypes. This complexity suggests that BBB-related alterations may interact with broader systemic, developmental and disorder-specific mechanisms, underscoring the need for longitudinal and multimodal studies to reconcile these differences.

These findings are not directly generalizable to ADHD. We cite them to illustrate that alterations in claudin-5 and β-catenin have been observed across multiple neurodevelopmental and psychiatric disorders, potentially reflecting shared neuroinflammatory or neurovascular mechanisms. For example, altered claudin-5 expression has been demonstrated in postmortem prefrontal cortex tissue in patients with schizophrenia, with concurrent evidence linking its dysregulation to blood–brain barrier dysfunction and immune-related changes (Nishiura et al., 2017). In parallel, there is substantial literature implicating dysregulation of the Wnt/β-catenin pathway in neurodevelopmental and psychiatric conditions, including schizophrenia and autism spectrum disorders (Vallée, 2022; Zhuang et al., 2023). These parallels should be regarded as hypothesis-generating, and direct mechanistic studies in ADHD populations are warranted to clarify their relevance.

There are very few studies on the relationship between paxillin and psychiatric disorders. In a recent study conducted in children with ASD, no significant difference was found between the study groups in paxillin levels (Bilgic et al., 2023). Similarly, no statistically significant difference was found between the ADHD group and the control group in our study. Although these results suggest that paxillin does not play a role in the etiopathogenesis of ADHD, there is a need for further research on this subject which has very little data.

Taken together, while our findings highlight potential alterations in BBB-related proteins in children with ADHD, it is important to consider these results within a broader biological context. In addition to their involvement in blood-brain barrier integrity, claudin-5 and β-catenin have diverse roles beyond the CNS vasculature. Claudin-5 is critical for vascular barrier function in various peripheral tissues and may participate in systemic inflammatory responses that can influence neurodevelopment and psychiatric outcomes (Greene et al., 2019; Kakogiannos et al., 2020). β-catenin, a key mediator of the Wnt signaling pathway, also regulates cell adhesion, synaptic plasticity and immune system functions (Maguschak & Ressler, 2012; Pai et al., 2017). Dysregulation of these pathways has been implicated in multiple neurodevelopmental and psychiatric disorders, including autism spectrum disorder, schizophrenia and mood disorders (Bilgic et al., 2023; Teo et al., 2018; Vallée, 2022). Therefore, the altered serum levels of these proteins observed in our study may reflect a combination of BBB-related alterations and broader systemic or neurodevelopmental processes. This underscores the need to interpret our findings with caution, appreciating the complex and multifaceted nature of these molecular changes.

Limitations/Future Directions

Our study is the first to present data on β-catenin and paxillin levels in individuals with ADHD; however, several limitations should be considered when interpreting these findings. First, the sample size was relatively moderate. Although claudin-5 and β-catenin are highly relevant to BBB structure and function, they are not exclusively expressed in the CNS, and peripheral tissues may also contribute to their serum levels. Consequently, the tissue origin of the observed changes cannot be determined. Moreover, given the multifunctional nature of β-catenin, its elevation in serum could also reflect peripheral Wnt pathway activation, immune processes or developmental changes, and should not be interpreted as a BBB-specific alteration in isolation. Importantly, we did not include direct or surrogate measures of BBB integrity (e.g., albumin quotient, neuroimaging-based permeability assessment and cognitive markers), nor CNS-specific biomarkers (e.g., cerebrospinal fluid analysis and endothelial cell–derived exosome profiling), which limits the ability to confirm BBB involvement. Additionally, no significant correlations were found between biomarker levels and ADHD symptom severity or comorbid symptoms, suggesting that these molecules may reflect peripheral or non-specific processes rather than ADHD-specific mechanisms. Finally, our study does not establish whether serum claudin-5 and β-catenin levels correspond to concentrations at the BBB or in brain tissue, further constraining their interpretation as direct markers of CNS-specific changes.

In conclusion, this study provided important data on the possible roles of claudin-5, β-catenin and paxillin in the etiopathogenesis of ADHD. Changes in these molecules may lead to structural disruptions in the CNS, affecting processes such as cell maturation and adhesion in the central nervous system and disrupting the neuronal development process. These disruptions may also be effective in the etiopathogenesis of ADHD. Future studies to be planned in a longitudinal design with a larger sample by addressing the limitations of our study will provide valuable data on the role of the mentioned parameters in the formation of ADHD.

Footnotes

ORCID iD

Necati Uzun

Ethical Considerations

Approval for this study was obtained from Ethics Committee of Necmettin Erbakan University with the decision number (2021/3225).

Consent to Participate

Verbal and informed written consent was obtained from the parents of all participants.

Author Contributions

Conception or design of the work: Necati Uzun, Ayhan Bilgiç and İbrahim Kılınç. Data collection: Hurşit Ferahkaya, Mehmet Berat Taş, İbrahim Kılınç and Ahmet Osman Kılıç. Data analysis and interpretation: Necati Uzun and Ayhan Bilgiç. Drafting the article: Necati Uzun, Ayhan Bilgiç and Hurşit Ferahkaya. Critical revision of the article: Necati Uzun and Hurşit Ferahkaya. Final approval of the version to be published Necati Uzun and Hurşit Ferahkaya.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Funding for this study was provided by a grant from the Necmettin Erbakan University Scientific Research Projects Unit within the scope of project number 211218019.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

The dataset of the study is available on request from the corresponding author.

Author Biographies

Necati Uzun is an Associate Professor of Child and Adolescent Psychiatry whose academic and clinical work primarily focuses on Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD). He serves as both a clinician and faculty member at Necmettin Erbakan University, Meram Medical School, where he continues to contribute to research, education, and clinical practice.

Ayhan Bilgiç is a Professor of Child and Adolescent Psychiatry with longstanding research and clinical interests in Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD). He maintains an active clinical practice in his private clinic and pursues his academic work at İzmir University of Economics, where he is engaged in research and teaching.

Hurşit Ferahkaya is an Assistant Professor in Child and Adolescent Psychiatry, specializing in academic and clinical work related to Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD). He works as both an educator and a clinician at Necmettin Erbakan University, Meram Medical School.

Mehmet Berat Taş is an Assistant Professor of Child and Adolescent Psychiatry whose scholarly and clinical endeavors concentrate on Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD). He fulfills dual roles as a clinician and academic staff member at Karamanoğlu Mehmetbey University.

İbrahim Kılınç is an Associate Professor of Medical Biochemistry conducting research on neurological, psychiatric, and endocrine disorders. His work spans molecular mechanisms, biomarker studies, and translational research aimed at understanding complex biological processes underlying these conditions.

Ahmet Osman Kılıç is an Associate Professor of Pediatrics whose academic and clinical interests include pediatric emergency care, general pediatrics, and pediatric intensive care. He works both as a clinician and academic faculty member at Necmettin Erbakan University, Meram Medical School, contributing to patient care, education, and research.

References

Abu-Elfotuh

Abdel-Sattar

S. A.

Abbas

A. N.

Mahran

Y. F.

Alshanwani

A. R.

Hamdan

A. M. E.

Atwa

A. M.

Reda

Ahmed

Y. M.

Zaghlool

S. S.

El-Din

M. N.

(2022). The protective effect of thymoquinone or/and thymol against monosodium glutamate-induced attention-deficit/hyperactivity disorder (ADHD)-like behavior in rats: Modulation of Nrf2/HO-1, TLR4/NF-κB/NLRP3/caspase-1 and Wnt/β-Catenin signaling pathways in rat model. Biomedicine & Pharmacotherapy, 155, Article 113799. https://doi.org/10.1016/j.biopha.2022.113799

American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders, 5th edition: DSM-5. American Psychiatric Publishing.

Aydoğan Avşar

Işık

Ü.

Aktepe

Kılıç

Doğuç

DK.

(2020). Serum zonulin and claudin-5 levels in children with attention-deficit/hyperactivity disorder. International Journal of Psychiatry in Clinical Practice, 25, 49–55.

Bilgic

Ferahkaya

Karagoez

Kılınç

İ.

Energin

V. M.

(2023). Serum claudin-5, claudin-11, occludin, vinculin, paxillin, and beta-catenin levels in preschool children with autism spectrum disorder. Nordic Journal of Psychiatry, 77(5), 506–511.

Caracci

M. O.

Avila

M. E.

De Ferrari

G. V.

(2016). Synaptic Wnt/GSK3 β signaling hub in autism. Neural Plasticity, 2016, Article 9603751.

Chandrakesan

Jakkula

L. U. M. R.

Ahmed

Roy

Anant

Umar

(2013). Differential effects of β-catenin and NF-κB interplay in the regulation of cell proliferation, inflammation and tumorigenesis in response to bacterial infection. PLoS ONE, 8(11), e79432. https://doi.org/10.1371/journal.pone.0079432

Custodio

R. J. P.

Kim

H. J.

Kim

Ortiz

D. M.

Kim

Buctot

Sayson

L. V.

Lee

H. J.

Kim

B.-N.

E. C.

Cheong

J. H.

(2023). Hippocampal dentate gyri proteomics reveals Wnt signaling involvement in the behavioral impairment in the THRSP-overexpressing ADHD mouse model. Communications Biology, 6(1), 55. https://doi.org/10.1038/s42003-022-04387-5

Deakin

N. O.

Turner

C. E.

(2008). Paxillin comes of age. Journal of Cell Science, 121(15), 2435–2444.

Ercan

E. S.

Amado

Somer

Çikoğlu

(2001). Development of a test battery for attention deficit hyperactivity disorder. Turkish Journal of Child and Adolescent Mental Health, 8, 132–144.

10.

Ferahkaya

Akça

Ö. F.

Baysal

Kılınç

. (2024). Claudin-5, occludin, zonulin and tricellulin levels of children with attention-deficit/hyperactivity disorder. The European Journal of Psychiatry, 38(1), Article 100225. https://doi.org/10.1016/j.ejpsy.2023.100225

11.

Gormez

Kılınçaslan

Orengul

A. C.

Ebesutani

Kaya

Ceri

Nasıroglu

Filiz

Chorpita

(2017). Psychometric properties of the Turkish version of the Revised Child Anxiety and Depression Scale – Child Version in a clinical sample. Psychiatry and Clinical Psychopharmacology, 27(1), 84–92. https://doi.org/10.1080/24750573.2017.1297494

12.

Greene

Hanley

Campbell

(2019). Claudin-5: Gatekeeper of neurological function. Fluids and Barriers of the CNS, 16(1), 3. https://doi.org/10.1186/s12987-019-0123-z

13.

Greene

Hanley

Campbell

(2020). Blood-brain barrier associated tight junction disruption is a hallmark feature of major psychiatric disorders. Translational Psychiatry, 10(1), 373. https://doi.org/10.1038/s41398-020-01054-3

14.

Greene

Kealy

Humphries

M. M.

Gong

Hou

Hudson

Cassidy

L. M.

Martiniano

Shashi

Hooper

S. R.

Grant

G. A.

Kenna

P. F.

Norris

Callaghan

C. K.

Islam

dN., O’Mara

S. M.

Najda

Campbell

S. G.

Pachter

J. S.

, . . . Campbell

(2018). Dose-dependent expression of claudin-5 is a modifying factor in schizophrenia. Molecular Psychiatry, 23(11), 2156–2166. https://doi.org/10.1038/mp.2017.156

15.

Işık

Ü.

Aydoğan Avşar

Aktepe

Doğuç

DK.

Kılıç

Büyükbayram

Hİ.

(2021). Serum zonulin and claudin-5 levels in children with obsessive–compulsive disorder. Nordic Journal of Psychiatry, 74(5), 346–351.

16.

Kakogiannos

Ferrari

Giampietro

Scalise

A. A.

Maderna

Ravà

Taddei

Lampugnani

M. G.

Pisati

Malinverno

Martini

Costa

Lupia

Cavallaro

Beznoussenko

G. V.

Mironov

A. A.

Fernandes

Rudini

Dejana

Giannotta

(2020). JAM-A acts via C/EBP-α to promote claudin-5 expression and enhance endothelial barrier function. Circulation Research, 127(8), 1056–1073. https://doi.org/10.1161/CIRCRESAHA.120.316742

17.

Kaufman

Birmaher

Brent

Rao

Flynn

Moreci

Williamson

Ryan

(1997). Schedule for affective disorders and schizophrenia for school-age children-present and lifetime version (K-SADS-PL): Initial reliability and validity data. Journal of the American Academy of Child & Adolescent Psychiatry, 36(7), 980–988. https://doi.org/10.1097/00004583-199707000-00021

18.

Kılıç

Işık

Ü.

Demirdaş

Doğuç

. (2020). Serum zonulin and claudin-5 levels in patients with bipolar disorder. Journal of Affective Disorders, 266, 37–46.

19.

Lizano

Pong

Santarriaga

Bannai

Karmacharya

(2023). Brain microvascular endothelial cells and blood-brain barrier dysfunction in psychotic disorders. Molecular Psychiatry, 28(9), 3698–3708. https://doi.org/10.1038/s41380-023-02255-0

20.

Zhang

Shu

Chen

Zhou

(2016). The neonatal levels of TSB, NSE and CK-BB in autism spectrum disorder from Southern China. Translational Neuroscience, 7(1), 6–11. https://doi.org/10.1515/tnsci-2016-0002

21.

Hammes

S. R.

(2018). Paxillin actions in the nucleus. Steroids, 133, 87–92. https://doi.org/10.1016/j.steroids.2017.10.012

22.

MacDonald

B. T.

Tamai

(2019). Wnt/beta-catenin signaling: Components, mechanisms, and diseases. Developmental Cell, 17, 9–26.

23.

Maes

Sirivichayakul

Kanchanatawan

Vodjani

(2019). Breakdown of the paracellular tight and adherens junctions in the gut and blood brain barrier and damage to the vascular barrier in patients with deficit Schizophrenia. Neurotoxicity Research, 36(2), 306–322. https://doi.org/10.1007/s12640-019-00054-6

24.

Maguschak

K. A.

Ressler

K. J.

(2012). The dynamic role of beta-catenin in synaptic plasticity. Neuropharmacology, 62(1), 78–88. https://doi.org/10.1016/j.neuropharm.2011.08.032

25.

McCullumsmith

R. E.

Gupta

Beneyto

Kreger

Haroutunian

Davis

K. L.

Meador-Woodruff

J. H.

(2007). Expression of transcripts for myelination-related genes in the anterior cingulate cortex in schizophrenia. Schizophrenia Research, 90(1–3), 15–27. https://doi.org/10.1016/j.schres.2006.11.017

26.

Najjar

Pahlajani

De Sanctis

Stern

J. N. H.

Najjar

(2017). Neurovascular unit dysfunction and blood–brain barrier hyperpermeability contribute to schizophrenia neurobiology: A theoretical integration of clinical and experimental evidence. Frontiers in Psychiatry, 8, 83.

27.

Nishiura

Ichikawa-Tomikawa

Sugimoto

Kunii

Kashiwagi

Tanaka

Chiba

(2017). PKA activation and endothelial claudin-5 breakdown in the schizophrenic prefrontal cortex. Oncotarget, 8(55), 93382.

28.

Omidinia

Mazar

F. M.

Shahamati

Ianmehr

Mohammadi

H. S.

(2014). Polymorphism of the CLDN5 gene and schizophrenia in an Iranian population. Iranian Journal of Public Health, 43(1), 79.

29.

Pai

S. G.

Carneiro

B. A.

Mota

J. M.

Costa

Leite

C. A.

Barroso-Sousa

Kaplan

J. B.

Chae

Y. K.

Giles

F. J.

(2017). Wnt/beta-catenin pathway: Modulating anticancer immune response. Journal of Hematology & Oncology, 10(1), 101. https://doi.org/10.1186/s13045-017-0471-6

30.

Pandey

G. N.

Rizavi

H. S.

Tripathi

Ren

(2015). Region-specific dysregulation of glycogen synthase kinase-3β and β-catenin in the postmortem brains of subjects with bipolar disorder and schizophrenia. Bipolar Disorders, 17(2), 160–171.

31.

Polanczyk

G. V.

Salum

G. A.

Sugaya

L. S.

Caye

Rohde

L. A.

(2015). Annual Research Review: A meta-analysis of the worldwide prevalence of mental disorders in children and adolescents. Journal of Child Psychology and Psychiatry, 56(3), 345–365. https://doi.org/10.1111/jcpp.12381

32.

Santos

Linker

S. B.

Stern

Mendes

A. P. D.

Shokhirev

M. N.

Erikson

Randolph-Moore

Racha

Kim

Kelsoe

J. R.

Bang

A. G.

Alda

Marchetto

M. C.

Gage

F. H.

(2021). Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients. Molecular Psychiatry, 26(6), 2440–2456. https://doi.org/10.1038/s41380-020-00981-3

33.

Tanir

Orengul

A. C.

Ozdemir

Y. E.

Karayagmurlu

Bilbay Kaynar

Baki

A. M.

Vural

Coskun

(2023). Serum Zonulin and Claudin-5 but not interferon-gamma and interleukin-17A levels increased in children with specific learning disorder: A case–control study. Psychiatry and Clinical Psychopharmacology, 33, 211–217. https://doi.org/10.5152/pcp.2023.23660

34.

Teo

C. H.

Soga

Parhar

I. S.

(2018). Brain beta-catenin signalling during stress and depression. Neurosignals, 26(1), 31–42. https://doi.org/10.1159/000487764

35.

Thapar

Cooper

(2016). Attention deficit hyperactivity disorder. The Lancet, 387(10024), 1240–1250.

36.

Türkoğlu

(2014). Diagnosis of patients referring to a child and adolescent psychiatry outpatient clinic. Selcuk Medical Journal, 30(3), 118–122.

37.

Ünal

Öktem

Çetin Çuhadaroğlu

Çengel Kültür

S. E.

Akdemi

Foto Özdemir

Kalayci

B. M.

(2019). Reliability and validity of the schedule for affective disorders and schizophrenia for school-age children-present and lifetime version, DSM-5 November 2016-Turkish adaptation (K-SADS-PL-DSM-5-T). Turkish Journal of Psychiatry, 30(1), 42–50.

38.

Usta

Kılıç

Demirdaş

Işık

Ü.

Doğuç

D. K.

Bozkurt

(2021). Serum zonulin and claudin-5 levels in patients with schizophrenia. European Archives of Psychiatry and Clinical Neuroscience, 271(4), 767–773. https://doi.org/10.1007/s00406-020-01152-9

39.

Vallée

(2022). Neuroinflammation in schizophrenia: The key role of the WNT/β-catenin pathway. International Journal of Molecular Sciences, 23(5), 2810. https://doi.org/10.3390/ijms23052810

40.

Yde Ohki

C. M.

Grossmann

Alber

Dwivedi

Berger

Werling

A. M.

Grünblatt

(2020). The stress–Wnt-signaling axis: A hypothesis for attention-deficit hyperactivity disorder and therapy approaches. Translational Psychiatry, 10(1), 315.

41.

Zhang

(2021). The correlation between LncRNA-17A expression in peripheral blood mononuclear cells and Wnt/β-catenin signaling pathway and cognitive function in patients with Alzheimer disease. American Journal of Translational Research, 13(10), 11981–11986.

42.

Zhuang

Wang

Song

Tan

(2023). CTNNB1 in neurodevelopmental disorders. Frontiers in Psychiatry, 14, Article 1143328. https://doi.org/10.3389/fpsyt.2023.1143328