» Articles » PMID: 28449558

Model-driven Assessment of the Effects of Brain-derived Neurotrophic Factor Deficiency on Glutamate and Gamma-Aminobutyric Acid: Implications for Understanding Schizophrenia Pathophysiology

Overview
Specialty Psychiatry
Date 2017 Apr 29
PMID 28449558
Citations 4
Authors
Affiliations
Soon will be listed here.
Abstract

Objective: Deficient brain-derived neurotrophic factor (BDNF) is one of the important mechanisms underlying the neuroplasticity abnormalities in schizophrenia. Aberration in BDNF signaling pathways directly or circuitously influences neurotransmitters like glutamate and gamma-aminobutyric acid (GABA). For the first time, this study attempts to construct and simulate the BDNF-neurotransmitter network in order to assess the effects of BDNF deficiency on glutamate and GABA.

Methods: Using CellDesigner, we modeled BDNF interactions with calcium influx via N-methyl-D-aspartate receptor (NMDAR)- Calmodulin activation; synthesis of GABA via cell cycle regulators protein kinase B, glycogen synthase kinase and β-catenin; transportation of glutamate and GABA. Steady state stability, perturbation time-course simulation and sensitivity analysis were performed in COPASI after assigning the kinetic functions, optimizing the unknown parameters using random search and genetic algorithm.

Results: Study observations suggest that increased glutamate in hippocampus, similar to that seen in schizophrenia, could potentially be contributed by indirect pathway originated from BDNF. Deficient BDNF could suppress Glutamate decarboxylase 67-mediated GABA synthesis. Further, deficient BDNF corresponded to impaired transport via vesicular glutamate transporter, thereby further increasing the intracellular glutamate in GABAergic and glutamatergic cells. BDNF also altered calcium dependent neuroplasticity via NMDAR modulation. Sensitivity analysis showed that Calmodulin, cAMP response element-binding protein (CREB) and CREB regulated transcription coactivator-1 played significant role in this network.

Conclusion: The study presents quantitative model of biochemical network constituting the key signaling molecules implicated in schizophrenia pathogenesis. It provides mechanistic insights into putative contribution of deficient BNDF towards alterations in neurotransmitters and neuroplasticity that are consistent with current understanding of the disorder.

Citing Articles

In the Brain of Phosphodiesterases: Potential Therapeutic Targets for Schizophrenia.

Barbagallo F, Assenza M, Messina A Clin Psychopharmacol Neurosci. 2025; 23(1):15-31.

PMID: 39820109 PMC: 11747726. DOI: 10.9758/cpn.24.1229.


Peripheral Blood Levels of Brain-Derived Neurotrophic Factor in Patients with First Episode Psychosis: A Systematic Review and Meta-Analysis.

Singh S, Roy D, Marzouk T, Zhang J Brain Sci. 2022; 12(4).

PMID: 35447946 PMC: 9027267. DOI: 10.3390/brainsci12040414.


The Ameliorative Effects of Isorhynchophylline on Morphine Dependence Are Mediated Through the Microbiota-Gut-Brain Axis.

Chen Z, Zhijie C, Yuting Z, Chan L, Shilin X, Qichun Z Front Pharmacol. 2021; 12:526923.

PMID: 34168553 PMC: 8218633. DOI: 10.3389/fphar.2021.526923.


Increased Neutrophil-lymphocyte and Platelet-lymphocyte Ratios in Male Heroin Addicts: A Prospective Controlled Study.

Cicek E, Demirel B, Cicek I, Kirac A, Eren I Clin Psychopharmacol Neurosci. 2018; 16(2):190-196.

PMID: 29739133 PMC: 5953019. DOI: 10.9758/cpn.2018.16.2.190.


The role of microbiota in the pathogenesis of schizophrenia and major depressive disorder and the possibility of targeting microbiota as a treatment option.

Lv F, Chen S, Wang L, Jiang R, Tian H, Li J Oncotarget. 2017; 8(59):100899-100907.

PMID: 29246029 PMC: 5725071. DOI: 10.18632/oncotarget.21284.

References
1.
Yoshii A, Constantine-Paton M . Postsynaptic BDNF-TrkB signaling in synapse maturation, plasticity, and disease. Dev Neurobiol. 2010; 70(5):304-22. PMC: 2923204. DOI: 10.1002/dneu.20765. View

2.
Duman R, Monteggia L . A neurotrophic model for stress-related mood disorders. Biol Psychiatry. 2006; 59(12):1116-27. DOI: 10.1016/j.biopsych.2006.02.013. View

3.
Huang E, Reichardt L . Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci. 2001; 24:677-736. PMC: 2758233. DOI: 10.1146/annurev.neuro.24.1.677. View

4.
Sivakumaran S, Hariharaputran S, Mishra J, Bhalla U . The Database of Quantitative Cellular Signaling: management and analysis of chemical kinetic models of signaling networks. Bioinformatics. 2003; 19(3):408-15. DOI: 10.1093/bioinformatics/btf860. View

5.
Tandon R, Keshavan M, Nasrallah H . Schizophrenia, "just the facts" what we know in 2008. 2. Epidemiology and etiology. Schizophr Res. 2008; 102(1-3):1-18. DOI: 10.1016/j.schres.2008.04.011. View