A novel microfluidic drug discovery platform for studying communication between synaptically connected neural networks

Research output: Contribution to journalConference Contribution

Abstract

Aims: Many in-vitro systems used during pre-clinical trials fail to recreate the biological complexity of the in-vivo neural microenvironment. Taking advantage of recent advances in microfluidic technology, we seek to develop a perfusion based drug discovery platform that is capable of high-throughput pharmacological profiling. This in turn will allow us to better understand how
drugs influence the communication between functionally connected neural networks.

Methods: Mixed primary hippocampal networks were grown in microfluidic devices with environmentally separated chambers that allow synaptic connections to be formed with each other via an array of microchannels. The perfusion of multiple compounds in one chamber was achieved using computer controlled fluid actuation connected to the inlets/outlets of the microfluidic device. Responses to perfusates from directly stimulated neurons and those synaptically connected were recorded using calcium imaging.

Results: Following live/dead assays, a flow rate of 4μl min-1 showed the greatest cell viability and was used for subsequent experiments. Subsequently, a glutamate concentration response curve following direct stimulation was obtained which revealed an EC50 = 4μM. Pharmacological manipulation of neuronal activity was also achieved as the neuronal response to glutamate was
reversibly reduced in the presence of ionotropic glutamatergic antagonists. Furthermore, repeated glutamate perfusions induced increasing levels of activity in the adjacent, naïve neural network.

Conclusion: The proposed microfluidic system is able to reliably produce pharmacological profiles for drugs in a neurological setting.
The novelty of the presented drug discovery platform is its ability to not only determine the properties of a new drug, but how the
drug influences communication between neural networks.

Fingerprint

Microfluidics
Neural networks
Communication
Microchannels
Neurons
Calcium
Assays
Cells
Flow rate
Throughput
Imaging techniques
Fluids
Drug Discovery
Experiments

Keywords

  • perfusion
  • microfluidic
  • neuronal networks
  • calcium Imaging
  • glutamate
  • neuronal communication
  • drug application

Cite this

@article{277f82f82eb74753862878c21c317bce,
title = "A novel microfluidic drug discovery platform for studying communication between synaptically connected neural networks",
abstract = "Aims: Many in-vitro systems used during pre-clinical trials fail to recreate the biological complexity of the in-vivo neural microenvironment. Taking advantage of recent advances in microfluidic technology, we seek to develop a perfusion based drug discovery platform that is capable of high-throughput pharmacological profiling. This in turn will allow us to better understand howdrugs influence the communication between functionally connected neural networks.Methods: Mixed primary hippocampal networks were grown in microfluidic devices with environmentally separated chambers that allow synaptic connections to be formed with each other via an array of microchannels. The perfusion of multiple compounds in one chamber was achieved using computer controlled fluid actuation connected to the inlets/outlets of the microfluidic device. Responses to perfusates from directly stimulated neurons and those synaptically connected were recorded using calcium imaging. Results: Following live/dead assays, a flow rate of 4μl min-1 showed the greatest cell viability and was used for subsequent experiments. Subsequently, a glutamate concentration response curve following direct stimulation was obtained which revealed an EC50 = 4μM. Pharmacological manipulation of neuronal activity was also achieved as the neuronal response to glutamate wasreversibly reduced in the presence of ionotropic glutamatergic antagonists. Furthermore, repeated glutamate perfusions induced increasing levels of activity in the adjacent, na{\"i}ve neural network.Conclusion: The proposed microfluidic system is able to reliably produce pharmacological profiles for drugs in a neurological setting.The novelty of the presented drug discovery platform is its ability to not only determine the properties of a new drug, but how thedrug influences communication between neural networks.",
keywords = "perfusion, microfluidic, neuronal networks, calcium Imaging, glutamate, neuronal communication, drug application",
author = "Christopher MacKerron",
year = "2017",
month = "4",
day = "7",
doi = "10.1177/2398212817705279",
language = "English",
volume = "1",
pages = "211--12",
journal = "Brain and Neuroscience Advances",
issn = "2398-2128",

}

A novel microfluidic drug discovery platform for studying communication between synaptically connected neural networks. / MacKerron, Christopher.

In: Brain and Neuroscience Advances, Vol. 1, P-T172, 07.04.2017, p. 211-12.

Research output: Contribution to journalConference Contribution

TY - JOUR

T1 - A novel microfluidic drug discovery platform for studying communication between synaptically connected neural networks

AU - MacKerron, Christopher

PY - 2017/4/7

Y1 - 2017/4/7

N2 - Aims: Many in-vitro systems used during pre-clinical trials fail to recreate the biological complexity of the in-vivo neural microenvironment. Taking advantage of recent advances in microfluidic technology, we seek to develop a perfusion based drug discovery platform that is capable of high-throughput pharmacological profiling. This in turn will allow us to better understand howdrugs influence the communication between functionally connected neural networks.Methods: Mixed primary hippocampal networks were grown in microfluidic devices with environmentally separated chambers that allow synaptic connections to be formed with each other via an array of microchannels. The perfusion of multiple compounds in one chamber was achieved using computer controlled fluid actuation connected to the inlets/outlets of the microfluidic device. Responses to perfusates from directly stimulated neurons and those synaptically connected were recorded using calcium imaging. Results: Following live/dead assays, a flow rate of 4μl min-1 showed the greatest cell viability and was used for subsequent experiments. Subsequently, a glutamate concentration response curve following direct stimulation was obtained which revealed an EC50 = 4μM. Pharmacological manipulation of neuronal activity was also achieved as the neuronal response to glutamate wasreversibly reduced in the presence of ionotropic glutamatergic antagonists. Furthermore, repeated glutamate perfusions induced increasing levels of activity in the adjacent, naïve neural network.Conclusion: The proposed microfluidic system is able to reliably produce pharmacological profiles for drugs in a neurological setting.The novelty of the presented drug discovery platform is its ability to not only determine the properties of a new drug, but how thedrug influences communication between neural networks.

AB - Aims: Many in-vitro systems used during pre-clinical trials fail to recreate the biological complexity of the in-vivo neural microenvironment. Taking advantage of recent advances in microfluidic technology, we seek to develop a perfusion based drug discovery platform that is capable of high-throughput pharmacological profiling. This in turn will allow us to better understand howdrugs influence the communication between functionally connected neural networks.Methods: Mixed primary hippocampal networks were grown in microfluidic devices with environmentally separated chambers that allow synaptic connections to be formed with each other via an array of microchannels. The perfusion of multiple compounds in one chamber was achieved using computer controlled fluid actuation connected to the inlets/outlets of the microfluidic device. Responses to perfusates from directly stimulated neurons and those synaptically connected were recorded using calcium imaging. Results: Following live/dead assays, a flow rate of 4μl min-1 showed the greatest cell viability and was used for subsequent experiments. Subsequently, a glutamate concentration response curve following direct stimulation was obtained which revealed an EC50 = 4μM. Pharmacological manipulation of neuronal activity was also achieved as the neuronal response to glutamate wasreversibly reduced in the presence of ionotropic glutamatergic antagonists. Furthermore, repeated glutamate perfusions induced increasing levels of activity in the adjacent, naïve neural network.Conclusion: The proposed microfluidic system is able to reliably produce pharmacological profiles for drugs in a neurological setting.The novelty of the presented drug discovery platform is its ability to not only determine the properties of a new drug, but how thedrug influences communication between neural networks.

KW - perfusion

KW - microfluidic

KW - neuronal networks

KW - calcium Imaging

KW - glutamate

KW - neuronal communication

KW - drug application

UR - https://www.bna.org.uk/meetings/bna2017/

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EP - 212

JO - Brain and Neuroscience Advances

T2 - Brain and Neuroscience Advances

JF - Brain and Neuroscience Advances

SN - 2398-2128

M1 - P-T172

ER -