Clin Psychopharmacol Neurosci.  2017 May;15(2):115-125. 10.9758/cpn.2017.15.2.115.

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

• Agrawal R
• Kalmady SV
• Venkatasubramanian G

• KMID: 2378479
• DOI: http://doi.org/10.9758/cpn.2017.15.2.115

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 in silico 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.

Keyword

Schizophrenia; Computer simulation; Signal transduction; Brain-derived neurotrophic factor; Neurotransmitter agents; Neuronal plasticity

MeSH Terms

Amino Acid Transport System X-AG
Brain-Derived Neurotrophic Factor*
Calcium
Calmodulin
Cell Cycle
Computer Simulation*
Cyclic AMP Response Element-Binding Protein
gamma-Aminobutyric Acid*
Glutamate Decarboxylase
Glutamic Acid*
Glycogen Synthase Kinases
Hippocampus
N-Methylaspartate
Neuronal Plasticity
Neurotransmitter Agents
Proto-Oncogene Proteins c-akt
Schizophrenia*
Signal Transduction
Transportation
Amino Acid Transport System X-AG
Brain-Derived Neurotrophic Factor
Calcium
Calmodulin
Cyclic AMP Response Element-Binding Protein
Glutamate Decarboxylase
Glutamic Acid
Glycogen Synthase Kinases
N-Methylaspartate
Neurotransmitter Agents
Proto-Oncogene Proteins c-akt
gamma-Aminobutyric Acid