Nagarah, John Michael

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John Michael Nagarah

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General Commentary
published: 23 November 2011
doi: 10.3389/fphar.2011.00074
Neurons on a chip – toward high throughput network and 
pharmacology investigations
John Michael Nagarah*
Broad Fellows Program, Division of Biology, California Institute of Technology, Pasadena, CA, USA
*Correspondence: jnagarah@caltech.edu
A commentary on
From understanding cellular function to 
novel drug discovery: the role of planar 
patch-clamp array chip technology
by Py, C., Martina, M., Diaz-Quijada, G. 
A., Luk, C. C., Martinez, D., Denhoff, M. 
W., Charrier, A., Comas, T., Monette, R., 
Krantis, A., Syed, N. I., and Mealing, G. A. R. 
(2011). Front. Pharmacol. 2:51. doi: 10.3389/
fphar.2011.00051
The biophysical properties of single neu-
rons and synaptic connections between 
populations of neurons enable the brain 
to form memories, make decisions, and 
perceive the surrounding environment. 
The ability of neurons to transmit signals 
is reliant on ion channel proteins embed-
ded in the plasma membrane (Hodgkin 
and Huxley, 1952; Koch, 2005). Ion channel 
defects and neural network dysfunction are 
the basis of several neurological disorders 
(Ackerman and Clapham, 1997; Palop et al., 
2006; Seeley et al., 2009). The development 
of new technologies, such as those men-
tioned within this issue, is fueled by the 
desire not only to understand the funda-
mental processes underlying neuronal sig-
nals, but also, to gain a better understanding 
of the causes, and thus potential treatments 
for neurological diseases.
Traditionally, ion channel protein 
activity in single cells has been monitored 
using the glass pipette patch-clamp tech-
nique (Hamill et al., 1981). Our detailed 
understanding of ion channel kinetics and 
pharmacological properties made possible 
by this technique is one of the reasons why 
so many drug targets include ion chan-
nels (Wang and Li, 2003). However, the 
patch-clamp technique has been limited 
by the number of cells from which it can 
simultaneously record. Recent advances 
in robotics have enabled measurements in 
brain slices from 12 simultaneous pipette 
patch-clamp electrodes, illustrating novel 
electrophysiological principles that govern 
network behavior, though these experi-
ments are still demanding on the user 
(Anastassiou et al., 2011). In contrast, 
multi-electrode arrays (MEAs) and sili-
con-based transistor arrays allow for extra-
cellular recordings from hundreds and 
thousands of electrodes simultaneously 
(Pine, 1980; Hutzler et al., 2006). Despite 
the limited amount of biophysical infor-
mation obtained from these  experiments, 
the high throughput of MEAs has enabled 
their successful use in discovering novel 
network mechanisms (Hosoya et al., 2005) 
and in screening potential pharmaceuti-
cal compounds (Hill et al., 2010; Redon 
et al., 2010). As each technique presents its 
own strengths and weaknesses, combining 
the throughput of the MEA platform with 
the resolution and control of the patch-
clamp would provide a unique hybrid that 
would be highly welcomed in many areas 
of neuroscience.
Recently, researchers have succeeded in 
replacing the glass pipette with a micro-
machined orifice in a planar substrate. 
Through their ability to achieve an elec-
trical resistance greater than 1 gigaohm 
between the cell membrane and pore, pla-
nar patch-clamp electrodes have enabled 
high quality electrophysiology recordings 
(Fertig et al., 2002; Nagarah et al., 2010). 
Automated patch-clamp (APC) systems 
have been used primarily for pharma-
ceutical screening against ion channels 
of interest expressed in cell lines. Only 
recently have APCs been used to investigate 
primary cells or physiologically more rel-
evant cells derived from pluripotent stem 
cells (Milligan et al., 2009; Stoelzle et al., 
2011). In this issue, Py et al. (2011) describe 
their success in integrating cultured neu-
rons onto planar patch-clamp electrodes. 
A significant accomplishment of theirs is 
obtaining gigaohm seals between poly-l-
lysine (PLL) coated apertures and cultured 
neurons. This is surprising consider-
ing the contamination susceptibility of 
patch-clamp electrodes, suggesting the 
sealing mechanism of suspended cells is 
different than that of cultured neurons. 
Their platform has allowed for intracel-
lular recordings of neuronal activity from 
cultured neurons and synapse forma-
tion on the chip, demonstrated by dual 
planar and pipette measurements along 
with pharmacological characterization. 
Simultaneous recordings from synapti-
cally connected neurons with dual planar 
electrodes have proven difficult so far, but 
nonetheless, they are able to record from 
multiple apertures simultaneously using 
an improved device fabrication scheme 
and microfluidic channels. The authors 
are also making advancements in chemi-
cal patterning methods to precisely localize 
neurons onto the planar orifices which will 
eliminate the need for manual placement.
While the bulk of recordings have 
been from snail neurons, the authors have 
recently integrated mammalian neurons 
onto their device, increasing the applica-
bility of this platform to drug screening. 
High throughput pharmaceutical screen-
ing on patch-clamped neuronal cultures 
will enable the observation of a drug’s 
effect on synaptic transmission as well as 
ion channel behavior. Additionally, the 
planar nature of the devices described 
here opens up the possibility of integrat-
ing with it other technologies. For exam-
ple, a novel microfluidic culture system 
has allowed for investigations of the cell 
biology of synaptic functions with high 
spatial and temporal resolution (Taylor 
et al., 2010). Combining a similar sys-
tem with planar patch-clamp electrodes 
would add electrophysiological control 
to cell biology experiments, and provide 
even more detail to synaptic dynamics 
investigations. Further development is 
still needed before such experiments are 
made possible, but Py et. al.’s efforts will 
undoubtedly contribute to the growing list 
www.frontiersin.org November 2011 | Volume 2 | Article 74 | 1
of tools that neuroscientists use to provide 
insight in neural computation, the nature 
of neurological diseases, and the treatment 
of diseases.
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Received: 10 October 2011; accepted: 06 November 2011; 
published online: 23 November 2011.
Citation: Nagarah JM (2011) Neurons on a chip – toward 
high throughput network and pharmacology investigations. 
Front. Pharmacol. 2:74. doi: 10.3389/fphar.2011.00074
This article was submitted to Frontiers in Pharmacology of 
Ion Channels and Channelopathies, a specialty of Frontiers 
in Pharmacology.
Copyright © 2011 Nagarah. This is an open-access article 
subject to a non-exclusive license between the authors and 
Frontiers Media SA, which permits use, distribution and 
reproduction in other forums, provided the original authors 
and source are credited and other Frontiers conditions are 
complied with.
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Py, C., Martina, M., Diaz-Quijada, G. A., Luk, C. C., 
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T., Monette, R., Krantis, A., Syed, N. I., and Mealing, G. 
A. R. (2011). From understanding cellular function to 
novel drug discovery: the role of planar patch-clamp 
array chip technology. Front. Pharmacol. 2:51. doi: 
10.3389/fphar.2011.00051
Redon, N., Lanneau, C., Cervello, P., Biton, B., Daniel, B., 
Oury-Donat, F., and Avenet, P. (2010). “Importanice 
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Nagarah Neurons on a chip
Frontiers in Pharmacology | Pharmacology of Ion Channels and Channelopathies November 2011 | Volume 2 | Article 74 | 2


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