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.
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

Objective: Schizophrenia is a disorder of language and self, with first-rank symptoms (FRS) as one of the predominant features in a subset of patients. Abnormal language lateralization is hypothesized to underlie the neurobiology of FRS in schizophrenia. The role of Broca’s area with its right-hemispheric counterpart, consisting of pars triangularis (PTr) and pars opercularis (POp) of the inferior frontal gyrus in FRS is undetermined. We compared the volumes and asymmetries of PTr & POp in anti-psychotic-naive schizophrenia patients with FRS (FRS[＋]) with those without FRS (FRS[−]) and healthy-controls (HC) using three dimensional, interactive, semi-automated volumetric morphometry. Methods: Antipsychotic naïve FRS(＋) (n = 27), FRS(−) (n = 24) and HC (n = 51) were carefully assessed with structured and semi-structured clinical tools. T1-weighted images were acquired in a 3T scanner. Volumes of regions of interest were measured independently for both sides using slicer-3D software, and asymmetry indices were calculated. Results: FRS(＋) but not FRS(−) had a significant volume deficit in right PTr after controlling for the potential confounding effects of age, sex, and intracranial volume (p = 0.029). There was a significant leftward asymmetry of PTr in patients with FRS (i.e., leftward asymmetry in patients) (p = 0.026). No significant volume/asymmetry abnormalities were observed in POp. Conclusion Study findings suggest reduced right PTr volume with leftward asymmetry to be associated with FRS in schizophrenia. This is consistent with the loss of Yakovlevian torque in schizophrenia. Role of PTr in the neurobiology of schizophrenia as a disorder of self, speech, and social cognition needs further systematic evaluation in future research.

Objective: Schizophrenia is a disorder of language and self, with first-rank symptoms (FRS) as one of the predominant features in a subset of patients. Abnormal language lateralization is hypothesized to underlie the neurobiology of FRS in schizophrenia. The role of Broca’s area with its right-hemispheric counterpart, consisting of pars triangularis (PTr) and pars opercularis (POp) of the inferior frontal gyrus in FRS is undetermined. We compared the volumes and asymmetries of PTr & POp in anti-psychotic-naive schizophrenia patients with FRS (FRS[＋]) with those without FRS (FRS[−]) and healthy-controls (HC) using three dimensional, interactive, semi-automated volumetric morphometry. Methods: Antipsychotic naïve FRS(＋) (n = 27), FRS(−) (n = 24) and HC (n = 51) were carefully assessed with structured and semi-structured clinical tools. T1-weighted images were acquired in a 3T scanner. Volumes of regions of interest were measured independently for both sides using slicer-3D software, and asymmetry indices were calculated. Results: FRS(＋) but not FRS(−) had a significant volume deficit in right PTr after controlling for the potential confounding effects of age, sex, and intracranial volume (p = 0.029). There was a significant leftward asymmetry of PTr in patients with FRS (i.e., leftward asymmetry in patients) (p = 0.026). No significant volume/asymmetry abnormalities were observed in POp. Conclusion Study findings suggest reduced right PTr volume with leftward asymmetry to be associated with FRS in schizophrenia. This is consistent with the loss of Yakovlevian torque in schizophrenia. Role of PTr in the neurobiology of schizophrenia as a disorder of self, speech, and social cognition needs further systematic evaluation in future research.