Drug testing complementary metal‐oxide‐semiconductor chip reveals drug modulation of transmitter release for potential therapeutic applications

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.

Quantifying neurotransmitter secretion at single-vesicle resolution using high-density complementary metal–oxide–semiconductor electrode array

“…Using the presented CMOS integrated electrochemical sensors, we are able to perform hundreds of amperometric recordings in minutes as opposed to weeks using the conventional CFE approach 26 . Significant cost reduction in instrumentation for quantal release analysis will allow the rapid evaluation of existing and emerging treatments for their molecular effects on exocytosis.…”

“…Despite the significance of the studies conducted and the discoveries made using amperometry, the CFE technique is labor-intensive 16 – 22 , time consuming 19 , 23 – 25 , and can take from weeks to several months 26 to research the effects of neurological diseases or pharmacological treatments. In these studies, it is important that amperometry is performed at the single-cell level to account for heterogeneity in the characteristics of quantal release among the cell population 3 , 27 .…”

“…Developed CMOS-based biosensors have demonstrated their parallel recording capabilities through the mapping of the concentration of ferricyanide across a 16 × 16 electrode array 30 , the diffusion of H 2 O 2 in a 32 × 32 electrode array 31 , and the flow injection of several analytes across a 128 × 128 electrode array 32 . Furthermore, these CMOS-based bioelectronic systems have been developed and used for high-throughput recordings of neurotransmitter secretion from bovine chromaffin cells with a 10 × 10 electrode array 26 , 28 and from human neuroblastoma cells (SH-SY5Y) using a 32 × 32 electrode array 29 . Using the 10 × 10 electrode array, the effects of the antidepressant drugs, bupropion and citalopram, on neurotransmitter secretion have been studied 26 .…”

“…Furthermore, these CMOS-based bioelectronic systems have been developed and used for high-throughput recordings of neurotransmitter secretion from bovine chromaffin cells with a 10 × 10 electrode array 26 , 28 and from human neuroblastoma cells (SH-SY5Y) using a 32 × 32 electrode array 29 . Using the 10 × 10 electrode array, the effects of the antidepressant drugs, bupropion and citalopram, on neurotransmitter secretion have been studied 26 .…”

“…With the low-noise amplifiers in the CMOS chip and the improved noise performance due to the new post-CMOS process, this work presents the first single-vesicle recordings from pheochromocytoma (PC-12) cells using monolithically integrated CMOS biosensors. The presented silicon-based bioelectronics system can capture a large pool of quantal events in the span of minutes, providing rapid results compared to the conventional amperometry technique that can take from weeks to months to amass a comparable dataset 26 . Using data collected from two experiments, the statistical analysis presented reveals the changes in the characteristics of vesicle-membrane fusion and neurotransmitter release between a control group and L-Dopa-treated group of PC-12 cells.…”