Role of Glutamate Receptor-related Biomarkers in the Etiopathogenesis of ADHD
Ebru Ulu1, Esra Demirci1, Elif Funda Sener2, Sevgi Özmen1, Melike Kevser Gul3, Reyhan Tahtasakal2, Fatma Dal2
1Department of Child and Adolescent Psychiatry, Erciyes University School of Medicine, Kayseri, Turkey
2Erciyes University Genome and Stem Cell Center (GENKOK), Department of Medical Biology, Erciyes University Faculty of Medicine, Kayseri, Turkey
3Department of Child and Adolescent Psychiatry, Kayseri City Hospital, Kayseri, Turkey
Correspondence to: Esra Demirci
Department of Child and Adolescent Psychiatry, Erciyes University School of Medicine, 38039-Melikgazi, Kayseri, Turkey
E-mail: esra_z_d_r@hotmail.com
ORCID: https://orcid.org/0000-0002-8424-4947
Received: January 18, 2023; Revised: March 28, 2023; Accepted: May 2, 2023; Published online: June 26, 2023.
© The Korean College of Neuropsychopharmacology. All rights reserved.

This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Objective: Pathways associated with glutamate receptors are known to play a role in the pathophysiology of attention-deficit hyperactivity disorder (ADHD). However, cyclin-dependent kinase 5 (CDK5), microtubule-associated protein-2 (MAP2), guanylate kinase-associated protein (GKAP), and postsynaptic density 95 (PSD95), all of which are biomarkers involved in neurodevelopmental processes closely related to glutamatergic pathways, have not previously been studied in patients with ADHD. The main purpose of this study was to evaluate the plasma levels of CDK5, MAP2, GKAP, and PSD95 in children with ADHD and investigate whether these markers have a role in the etiology of ADHD.
Methods: Ninety-six children with ADHD between 6 and 15 years of age and 72 healthy controls were included in the study. Five milliliters of blood samples were taken from all participants. The samples were stored at −80°C until analyzed by the enzyme-linked immunosorbent assay method.
Results: Statistically significantly lower CDK5 levels were observed in children with ADHD than in healthy controls (p = 0.037). The MAP2, GKAP, and PSD95 levels were found to be statistically significantly higher in the ADHD group than in healthy controls (p = 0.012, p = 0.009, and p = 0.024, respectively). According to binary regression analysis, CDK5 and MAP2 levels were found to be predictors of ADHD.
Conclusion: In conclusion, we found that a close relationship existed between ADHD and glutamatergic pathways, and low levels of CDK5 and high levels of MAP2 and GKAP played a role in the etiopathogenesis of ADHD.
Keywords: Children; ADHD; CDK5; MAP2; GKAP; PSD95
INTRODUCTION

Attention-deficit hyperactivity disorder (ADHD) is a multifactorial disease, and many genetic, psychosocial, and environmental factors play a role in its etiology [1]. Recent studies have emphasized that pathways associated with glutamate receptors may have a role in the etiology of many mental disorders, including ADHD [2]. Genetic studies on the relationship between the glutamate system and ADHD showed a relationship between copy number variations in metabotropic glutamate receptor genes (GRM) 1,5,7,8 and ADHD, which plays a role in neurogenesis, synaptic plasticity, synaptogenesis, and selective cell death [3]. Increased glutamate/glutamine levels in the prefrontal cortex (PFC) and striatum in ADHD patients, targeting glutamate receptors in PFC neurons with psychostimulants [4], N-methyl-D-aspartate (NMDA) receptor dysfunction in PFC in animal models [5], improvements of ADHD symptoms with NMDA receptor antagonist memantine in children, are the findings that support the role of the glutamate system in the etiology of ADHD [6].

Cyclin-dependent kinase 5 (CDK5), a member of the CDK family, plays an important role in the central nervous system [7]. The vast majority of physiological CDK5 substrates are associated with the neuronal cytoskeleton. This allows CDK5 to play an important role in neuronal development by regulating neuronal migration, neuronal growth, axon guidance, and synapse formation. CDK5 activity is important for neurotransmission, synaptic plasticity and homeostasis, drug addiction, and long-term behavioral changes [8]. CDK5 has also been shown to modulate synaptic plasticity and memory through the control of NMDA receptors (NMDARs) [9]. The CDK5 activity has been shown to increase in many neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease, amyotrophic lateral sclerosis, ischemic stroke, and epilepsy; this increase is destructive and neurotoxic. Also, the CDK5 activity has been shown to decrease significantly in various psychiatric diseases such as mental retardation, ADHD, and schizophrenia [7]. In a study on rats, the CDK5 levels in the PFC before and after the methylphenidate (MPH) treatment were found to be lower in the ADHD model before the treatment than in the control group. After the MPH treatment, the CDK5 level in the PFC was shown to increase more in the ADHD model than in the control group [10]. Another study on the effects of CDK5 on the etiology of ADHD examined the ADHD probands in 217 patients with ADHD and 250 control and found that the three variants that were predicted to affect transcription, rs2069454, rs2069456, and rs2069459, were biomorphic [11]. This study showed that CDK5 could affect the etiology of ADHD by reducing synaptic neurotransmission and be a useful target for therapeutic intervention [11]. Apart from these two, no other study investigated the relationship between ADHD and CDK5.

Microtubule-associated protein-2 (MAP2) is a binding protein that binds microtubules together and is particularly found in the perikaryon and dendrites [12]. The MAP2 protein is a very important brain protein involved in the restructuring of dendrites during neurogenesis, synapse formation, and learning and memory events [13]. MAP2 plays a key role in neuronal response to growth factors, neurotransmitters, synaptic activity, neurotoxins, growth, differentiation, and plasticity of neurons. The metabolism and distribution of MAP2 within neurons are modulated by the activation of glutamate receptors, which play an important role in many aspects of neuronal plasticity [14]. Some changes in MAP2 have been associated with neurodegenerative and psychiatric disorders. MAP2 staining has been reported to decrease in the subiculum and entorhinal cortex of patients with schizophrenia, and MAP2 decreases in the temporal and medial lobes in patients with the Lewy body variant of AD [15]. Another study compared the MAP2 serum levels in patients with bipolar depression before and after pregnanolone treatment and healthy controls and found that the MAP2 levels were higher in patients with bipolar depression [16]. However, no study has so far evaluated the MAP2 levels in serum or plasma in patients with ADHD.

Postsynaptic density (PSD), a specialized membrane structure located at the dendritic spine ends of excitatory synapses, serves as the central channel for the transmission of neuronal signals. Postsynaptic density 95 (PSD95) and guanylate kinase-associated protein (GKAP) are cytoskeletal proteins involved in the PSD structure [17,18]. These proteins hold PSD together by binding to glutamate receptors, other postsynaptic receptors, adhesion molecules, cytoplasmic signaling enzymes, and cytoskeletal elements [17]. PSD95 has been associated with the synaptic plasticity of glutamatergic synapses during neurodevelopment due to its effects on NMDAR and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor, and synaptic plastic processes such as long-term potentiation and long-term depression have been shown to play a major role in the synaptic maturation of the dendritic spine [19]. In mouse studies, the deletion of the Discs Large MAGUK Scaffold Protein 4 (DLG4) gene, coding PSD95, has been shown to cause behavioral abnormalities such as increased repetitive behavior, decreased voice, and disordered social interactions consistent with the phenotypes observed in patients with autism spectrum disorder [20]. In addition, in a genetic study, DLG4 was identified as a candidate gene for the emergence of mental retardation as a result of reducing dendritic extensions [21]. Due to its interaction with PSD 95, GKAP encoded by Disks large-associated protein 1 (DLGAP1) could be effective in psychiatric diseases in which learning is cognitively impaired [22]. The GKAP protein (SAPAP1) encoded by DLGAP1 has been reported to interact with PSD95, which is encoded by DLG4 and reported to be a predictor of cognitive deficits; also, the DLGAP1–DLG4–NMDA complex may play a role in cognitive functions [23].

In conclusion, in our study, considering that ADHD is a neurodevelopmental disorder in which the glutamatergic system is also affected, the roles of CDK5, MAP2, GKAP, and PSD95 (which interact with glutamate receptors in different ways and also take part in the neurodevelopmental process) in the etiopathogenesis of ADHD were investigated.

METHODS

Participants

The 96 participants were selected from newly diagnosed, medication-free children (aged 6−15) diagnosed with ADHD according to The Diagnostic and Statistical Manual of Mental Disorders (DSM)-V diagnostic criteria and also 72 healthy volunteers among children and adolescents who applied to the Erciyes University Faculty of Medicine, Child and Adolescent Psychiatry Outpatient Clinic were included as controls. Children with substance use or addiction, with any known neurological, metabolic, and endocrine diseases, with mental retardation, who have had an acute infection in the last 1 month or have chronic infection were excluded. Children were included in the study after obtaining their verbal consent and their parents’ written and verbal consent. Ethics committee approval was obtained for the study from the Erciyes University Clinical Research Ethics Committee, dated 23.10.2019, and numbered 2019/731.

Clinical Assessment

The current DSM-V diagnoses were determined by applying the Affective Disorders and Schizophrenia Interview Schedule for School-age Children-Present and Lifetime Version (K-SADS-PL) to all children. The diagnosis of ADHD was made by two independent child and adolescent psychiatrists. Conner’s parent rating scale (CPRS) was used to assess the severity of the disorder. Sociodemographic data were obtained from all participants. Children with any psychiatric diagnosis other than ADHD were excluded except for children with mild anxiety, enuresis, encopresis, basic tic disorder, and language disorders (Table 1).

Blood Samples

Five milliliters of venous blood samples were taken from the participants in anticoagulant tubes, between 08:00 and 09:00 in the morning, for measuring CDK5, MAP2, 24OHC, GKAP, and PSD95. After centrifugation, the plasma was separated from all the samples and stored at −80°C until the analysis. The levels of CDK5 (SunRed 201-12-0782), MAP2 (SunRed 201-12-1310), 24OHC (SunRed 201-12-5376), GKAP (SunRed 201-12-8851), and PSD95 (SunRed 201-12-7263) were measured using an enzyme-linked immunosorbent assay kit according to the manufacturers’ instructions. After washing the plates and addition of Chromogen solution A, B, optical density values were measured for calculation of all protein concentrations of the samples at 450 nm (Promega Glumax Multi Detection System). All values were expressed in ng/ml.

Statistical Analysis

Data were analyzed by the Statistical Package for Social Sciences (SPSS) for Windows version 25 (IBM SPSS Inc.) program. After examining the distribution of the data with the Shapiro–Wilk test, numerical variables with normal distribution were expressed as mean ± standard deviation, and those with abnormal distribution were expressed as median (first to the third quarter). Categorical variables were represented as n (%). The chi-square test was used to compare the categorical variables between the two groups, and the Mann–Whitney Utest was used to compare the numerical variables. A comparison of numerical variables in more than two groups was made with the Kruskal–Wallis test. Correlation analyses of non-normally distributed parameters were performed with the Spearman correlation test. The predictive effects of some parameters were evaluated with binary regression analysis methods. A p value less than 0.05 was considered significant in statistical analyses.

RESULTS

Our study included 96 children and adolescents with ADHD (22 attention-deficit dominant types, 74 combined types) diagnosed according to the DSM-V criteria and 72 healthy children and adolescents without any psychiatric diagnosis (Table 1). No statistically significant difference exists between the groups in terms of age and sex. Twenty-two patients (22.9%) had a predominant appearance of attention deficit and 74 (77.1%) had a combined presentation.

The CDK5 plasma levels were found to be statistically significantly lower in the ADHD group than in healthy controls (p = 0.037). The MAP2, GKAP, and PSD95 levels were found to be statistically significantly higher in the ADHD group than in healthy controls (p = 0.012, p = 0.009, and p = 0.024, respectively) (Table 2). A statistically significant positive correlation was found between the levels of each of CDK5, MAP2, GKAP, and PSD95 in the ADHD group and the control group (Tables 3, 4).

There was no correlation found between the CPRS and biomarkers (Table 3), on the other hand the regression model comprising age, sex, CDK5, MAP2, GKAP, and PSD95 showed that CDK5 and MAP2 were significant predictors of the development of ADHD (p < 0.001, p = 0.001). A decreased CDK5 level and an increased MAP2 level might be effective in the development of ADHD (Table 5).

Receiver operating characteristic curve analysis was used to evaluate the predictive power of CDK5 and MAP2 levels to diagnose ADHD. As an important result, CDK5 has a stronger predictive value for assessing ADHD, with a sensitivity (%) of 59.6, and a specificity (%) of 59.4 (p = 0.002) (Fig. 1) while MAP2 has a stronger predictive value for distinguishing the healthy from ADHD (p = 0.012) (Fig. 2).

DISCUSSION

A close relationship between ADHD and glutamate receptors has been demonstrated in studies examining genomic-based and candidate markers for the etiopathogenesis of ADHD [4-6]. Due to this close relationship between glutamate receptors and ADHD, the relationships between the biomarkers associated with glutamate receptors; CDK5, MAP2, 24-hydroxycholesterol, GKAP, PSD95, and ADHD were investigated in this study. Lower CDK5 level and higher MAP2 level compared to healthy controls might be effective in the development of ADHD, although they are not related with the severity of symtoms.

Few studies exist in the literature that revealed the relationship between CDK5 and ADHD. Krapacher et al. [24] reported that knockout mice with suppressed CDK5 activity exhibited hyperactivity, one of the main findings of ADHD. This study focused on the important role of CDK5 in dopaminergic neurotransmission and reported that hyperactivity developed in the dopaminergic system and a hyperactive behavioral phenotype occurred in its deficiency [24]. CDK5 knockout mice could be taken as a useful animal model in ADHD studies. Maitra et al. [11] investigated the relationship between CDK5 and ADHD since CDK5 has a function in cortical neuronal migration; their findings revealed the formation of filamentous actin skeleton, normal cell growth, and differentiation, and ADHD might occur with the delayed maturation of the brain. They analyzed eight functional CDK5 gene variants from 217 patients with ADHD probands and 215 healthy volunteers. The study stated that the three gene variants (rs2069454, rs2069456, and rs2069459) were biomorphic and might be associated with ADHD [11]. Considering that many more variants of CDK5 have not been studied in this study, stronger associations between CDK5 and ADHD were quite obvious. The authors commented that this relationship might contribute to the development of ADHD by causing decreased synaptic neurotransmission of decreased CDK5 activity in the neurodevelopmental process [11]. Drerup et al. [25] evaluated the activity in some parts of the brain in-vivo in mice lacking p35 from CDK5 cofactors and reported increased glucose utilization in the cerebral cortex, basal hyperactivity, and paradoxical decreased movement against chronic injection of cocaine or MPH compared with the control group. In another study, an increase in the incidence of ADHD was shown after exposure to neurotoxins, such as organophosphates, which cause dysregulation of CDK5 [26,27]. In our study, the CDK5 level was found to be significantly lower in patients with ADHD than in the control group. The logistic regression analysis showed that the decrease in the CDK5 level was a significant determinant of the onset of the disorder. CDK5 has a stronger predictive value for assessing ADHD under the value of 23.16. Our results, like those of other studies in the literature, show the important effect of the CDK5 level on the development of ADHD. Regular CDK5 activity is necessary for the maintenance of normal motor and emotional behavior.

MAP2, which has not yet been studied in patients with ADHD, is associated with some neurodegenerative and psychiatric disorders. Polymorphism in the gene of MAP1B, one of the MAP proteins, has been reported to cause poor working memory performance in young patients with ADHD [28]. The alteration in the MAP2 protein immunoreactivity in patients with schizophrenia is known as a distinctive feature [29]. Again, MAP2 levels were observed to be increased in the depressive period in bipolar patients [16]. In our study, the MAP2 levels were found to be significantly higher in patients with ADHD than in the control group, and an increase in the MAP2 levels in the logistic regression analysis was observed to be a significant variable in the onset of the disorder. It has a stronger predictive value for distinguishing healthy from ADHD under the value of 2.37. Higher levels of this protein which participates in neuronal cytoskeletal organization and dendritic structure and also which is necessary for healthy neuronal function and formation of synaptic connections may play a role in the development of ADHD. At this point, genetic and immune-histo-chemical studies examining the relationship between MAP2 and ADHD are needed to support our results and better understand the role of MAP2 role in the etiopathogenesis of ADHD.

Although no study directly evaluated the PSD95 levels in patients with ADHD, studies suggesting abnormalities in PSD95 levels in these patients do exist [30,31]. Ha et al. [32] reported that the calyon protein, by complexing with PSD95, physically decreased the surface levels of D1 dopamine receptors in the synaptic cleft and inhibits D1-mediated signaling and thus might play a role in the pathophysiology of diseases such as ADHD and schizophrenia that occur in disorders of this receptor function. Hong et al. [30], on the contrary, examined the Homer protein, which is a PSD protein located in the postsynaptic region of glutamatergic excitatory synapses, on an ADHD animal model and reported that the expression of Homer 1a and Homer 2a/b genes, which encode the Homer protein, was lower in the ADHD group. Xi et al. [33] observed that the DLG4 gene, which encodes the PSD95 protein, was less expressed than that in the control group in their study on children with ADHD. The results of this study suggested that PSD95, a PSD protein, might be effective in the pathogenesis of ADHD. According to our findings, the blood PSD95 level was found to be higher in patients with ADHD. In addition, a positive correlation was found between CDK5 levels, which we considered a significant parameter in the development of ADHD.

Another PSD protein, GKAP, is a candidate protein that may be effective in the development of ADHD, similar to PSD95. In their study on 763 patients with ADHD and 140 healthy controls, Fan et al. [23] investigated the relationship between the executive functions of patients and the DLGAP1 gene encoding the GKAP protein. They reported that any dysfunction in the DLGAP1 gene increased ADHD symptoms and led to abnormalities in executive functions. A positive relationship between the increased DLGAP1 gene expression and ADHD score has been emphasized [23]. In our study, the GKAP level was found to be significantly higher in the patient group. Like PSD95, the GKAP protein might also affect the development of ADHD by causing dysfunction in NMDARs, resulting in neurodevelopmental disorders that are effective in the pathogenesis of ADHD, abnormalities in neural stimulation inhibition, and dysfunction in attention pathways.

Conclusion

In this study, we suggested that a close relationship existed between ADHD and glutamatergic pathways based on low CDK5 levels, also high MAP2, PSD95, and GKAP levels which might play a role in the etiopathogenesis of ADHD. More studies are needed to understand the effects of these biomarkers in the neurodevelopmental process and the etiopathogenesis of ADHD.

Limitations

Our study has some limitations. The levels of the parameters we used in our study were evaluated only peripherally; levels in the central nervous system could not be determined. Besides, since this was a cross-sectional study, it could not be evaluated how these parameters changed with the treatment or with the progression of the disorder.

Conflicts of Interest

No potential conflict of interest relevant to this article was reported.

Author Contributions

Designed the study: Esra Demirci, Elif Funda Sener. Performed the experiments or case: Esra Demirci, Ebru Ulu, Melike Kevser Gul. Analyses of samples: Fatma Dal, Elif Funda Sener, Reyhan Tahtasakal. Analyzed the data: Esra Demirci, Elif Funda Sener, Ebru Ulu, Sevgi Özmen, Melike Kevser Gul. Wrote the paper: Esra Demirci, Ebru Ulu. All authors have read and approved the final manuscript.

Figures
Fig. 1. Receiver operating characteristic (ROC) curve. ROC curve of CDK5 levels for assessment of ADHD/Healthy.
CDK5, cyclin-dependent kinase 5; ADHD, attention-deficit hyperactivity disorder; AUC, area under the curve.
Fig. 2. Receiver operating characteristic (ROC) curve. ROC curve of MAP2 levels for assessment of Healthy/ADHD.
MAP2, microtubule-associated protein-2; ADHD, attention-deficit hyperactivity disorder; AUC, area under the curve.
Tables

Demographic and characteristics of participants

Variables Patient group (n = 96) Control group (n = 72) p value
Age (yr) 8.77 ± 2.41 9.13 ± 2.44 0.297*
Sex
Female 23 (24.0) 22 (30.6) 0.339**
Male 73 (76.0) 50 (69.4)
Comorbidity
Anxiety 5 (5.2)
Enuresis 3 (3.1)
Tic disorder 5 (5.2) -
Encopresis 1 (1.0)
Language disorders 1 (1.0)
ADHD presentation
Attention-deficit 22 (22.9)
Combined 74 (77.1)
WISC-R total points 113.02 ± 16.05 116.78 ± 13.25 0.079*
CPRS 50.58 ± 20.65 -

Values are presented as mean ± standard deviation or number (%).

ADHD, attention-deficit hyperactivity disorder; WISC-R, Wechsler Intelligence Scale for Children-Revised; CPRS, Conners’ parent rating scale.

*Independent ttest, **Chi-square test.

Comparison of glutamate-associated biomarkers between groups

Variables Patient group
(n = 96)
Control group
(n = 72)
p value*
CDK5 (ng/ml) 22.48 (18.71/35.41) 25.15 (22.29/31.20) 0.037
MAP2 (ng/ml) 2.86 (1.41/7.69) 1.89 (1.08/4.09) 0.012
GKAP (ng/L) 2.98 (2.47/4.63) 2.60 (2.38/3.27) 0.009
PSD95 (pg/ml) 1.85 (1.59/2.84) 1.70 (1.53/2.16) 0.024

Values are presented as median (first quarter/third quarter).

CDK5, cyclin-dependent kinase 5; MAP2, microtubule-associated protein-2; GKAP, guanylate kinase-associated protein; PSD95, postsynaptic density 95.

*Mann–Whitney Utest.

Correlation of biomarkers in patients with ADHD

Variables CDK5 MAP2 GKAP CPRS
CDK5 - r = 0.901 r = 0.871 r = −0.153
p < 0.001 p < 0.001 p = 0.173
MAP2 r = 0.901 - r = 0.935 r = −0.128
p < 0.001 p < 0.001 p = 0.255
GKAP r = 0.871 r = 0.935 - r = −0.048
p < 0.001 p < 0.001 p = 0.672
PSD95 r = 0.911 r = 0.961 r = 0.941 r = −0.137
p < 0.001 p < 0.001 p < 0.001 p = 0.223

ADHD, attention-deficit hyperactivity disorder; CDK5, cyclin- dependent kinase 5; MAP2, microtubule-associated protein-2; GKAP, guanylate kinase-associated protein; PSD95, postsynaptic density 95.

Spearman correlation test. r = correlation coefficient.

Correlation of biomarkers in the control group

Variables CDK5 MAP2 GKAP
CDK5
MAP2 r = 0.903
p < 0.001
GKAP r = 0.854 r = 0.882
p < 0.001 p < 0.001
PSD95 r = 0.932 r = 0.926 r = 0.882
p < 0.001 p < 0.001 p < 0.001

CDK5, cyclin-dependent kinase 5; MAP2, microtubule-associated protein-2; GKAP, guanylate kinase-associated protein; PSD95, postsynaptic density 95.

Spearman correlation test. r = correlation coefficient.

Predictive of ADHD according to the binary logistic regression model

Variables B Odds ratio (95% confidence interval) p value
Age −0.134 0.875 (0.711−1.075) 0.162
Sex −0.343 0.710 (0.208−2.418) 0.655
CDK5 0.996 2.627 (1.960−3.521) < 0.001
MAP2 −1.930 0.145 (0.047−0.451) 0.001
GKAP −2.939 0.230 (0.15−3.586) 0.230
PSD95 −7.653 0.053 (0.01−5.586) 0.216

ADHD, attention-deficit hyperactivity disorder; CDK5, cyclin- dependent kinase 5; MAP2, microtubule-associated protein-2; GKAP, guanylate kinase-associated protein; PSD95, postsynaptic density 95.

X2(6) = 128.261, p < 0.001, Nagelkerke R Square: 0.771, 90.5%.

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