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2018 Abstracts

Task-based model of NMDA-mediated synaptic dysfunction and its relation to antipsychotics

Lucas Pinto, Brigham Young University

About 1 in 6 adults in the US use antipsychotics, the vast majority of these being long-term users [1]. Much is known about how these drugs affect extrapyramidal and pathophysiological symptoms [2], however little to nothing is known about how they affect long-term synaptic transmission in task-dependent working memory areas. Antipsychotics alter long-range synaptic functions in a distributed brain system, and most efforts in the literature thus far have been focused primarily on attempting to understand pathophysiological synaptic dysfunction (with and without drugs) at a local level, typically involving one sub region of the brain [3]. We propose a biophysically plausible computational model that captures (a) the anti-correlation between default-mode and task-dependent states in a spiking neural network at a global scale and (b) allows for direct implementation of pharmaceuticals. Our validating computational model is a spiking neural network consisting of, but not limited to, the working memory (WM) and default-mode network (DMN) regions in the brain. The model was designed in part using the brian simulator [5], and our specified AMPA, NMDA, GABA, D1 and D2 cell types within the model. Each cell is defined by a differential equation which captures these channel’s unique features [6], and constant parameter values which do not change on input or output. Capacitance values were determined from voltage clamp data in the literature. For our work with schizophrenia, we use ketamine-like effects [7] to induce the pathophysiological brain. Our lab is currently using this model to understand the blood oxygen level dependent activation of WM areas for patients with schizophrenia who are taking antipsychotics. 1. Moore TJ (2016) Adult Utilization of Psychiatric Drugs and Differences by Sex, Age, and Race. Jama Internal Medicine 177(2):274-275 2. Singh KP, et al. (2016) Effect of in utero exposure to the atypical antipsychotic risperidone on histopathological features of the rat placenta. Int J Exp Path. 97(7):125-32 3. Bremner JD, et al. (1998) Measurement of dissociative states with the Clinician- Administered Dissociative States Scale (CADSS). J Trauma Stress 11:125–136. 4. Stimberg M, Goodman DFM, Benichoux V, Brette R (2014). Equation-oriented specification of neural models for simulations. Frontiers Neuroinf, doi: 10.3389/fninf.2014.00006. 5. Compte A. et al. (2000) Synaptic Mechanisms and Network Dynamics Underlying Spatial Working Memory in a Cortical Network Model. Cerebral Cortex 10:910-923 6. Kotermanski SE, Johnson JW (2009) Mg2+ imparts NMDA receptor subtype selectivity to the Alzheimer’s drug memantine. J Neurosci 29:2774–2779.