Abstract
Neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease, are considered incurable and significantly reduce the quality of life of the patients. A variety of drugs that modulate neurotransmitter levels have been used for the treatment of the neurodegenerative diseases but with limited efficacy. In this work, an amperometric complementary metal‐oxide‐semiconductor (CMOS) chip is used for high‐throughput drug testing with respect to the modulation of transmitter release from single vesicles using chromaffin cells prepared from bovine adrenal glands as a model system. Single chromaffin cell amperometry was performed with high efficiency on the surface‐modified CMOS chip and follow‐up whole‐cell patch‐clamp experiments were performed to determine the readily releasable pool sizes. We show that the antidepressant drug bupropion significantly increases the amount of neurotransmitter released in individual quantal release events. The antidepressant drug citalopram accelerates rapid neurotransmitter release following stimulation and follow‐up patch‐clamp experiments reveal that this is because of the increase in the pool of readily releasable vesicles. These results shed light on the mechanisms by which bupropion and citalopram may be potentially effective in the treatment of neurodegenerative diseases. These results demonstrate that the CMOS amperometry chip technology is an excellent tool for drug testing to determine the specific mechanisms by which they modulate neurotransmitter release.
Highlights
Disease (HD), depression is commonly found accompanying these diseases (Grimes et al 2012; Beglinger et al 2014; Cooney and Stacy 2016; Aboukarr and Giudice 2018), making the treatment more complex
To trap cells individually in these microwells, chromaffin cells were cultured on chip and the cell culture media was exchanged with standard buffer after the cells had settled in the microwells (Fig. 1b and c)
Following acquisition of the microscope images, the complementary metal-oxide-semiconductor (CMOS) integrated circuit (IC) sensor was plugged into a self-assembled data acquisition device for amperometry recordings (Fig. 1d) and the cells were stimulated by application of high [K+]
Summary
Disease (HD), depression is commonly found accompanying these diseases (Grimes et al 2012; Beglinger et al 2014; Cooney and Stacy 2016; Aboukarr and Giudice 2018), making the treatment more complex. It has been reported that bupropion is an effective drug for the treatment of PD for some patients (Cooney and Stacy 2016). Citalopram is considered a selective serotonin reuptake inhibitor (Sindrup et al 1992; Tseng et al 2010; Cadeddu et al 2014) and restores short-term memory deficits in AD patients (Zhang et al 2018). While a few studies reported modulation of transmitter release in synaptosomes and in rat brain by bupropion or citalopram (Lin et al 2011; Cadeddu et al 2014), there are no studies investigating how bupropion and citalopram modulate frequency, quantal size, and kinetics of individual transmitter release events on a single-cell, single event level, and the relation of these mechanisms with the efficacy of neurodegenerative disease treatment
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