Changes in the intrinsic behavior of neurons

Researchers from Harvard's John Paulson School of Engineering and Applied Science (SEAS) and MIT have developed a new method to target diseased neurons in the brain and use light to alter their long-term behavior, paving the way
for potential new treatments for neurological disorders such as epilepsy and autism.

The study was published in the journal Science Advances
.

"We envision that this technique will provide new opportunities for high spatiotemporal resolution control of neurons in neuroscience and behavioral research, and develop new treatments for neurological diseases," said
Jia Liu, assistant professor of bioengineering and co-senior author of the study.

Optogenetics, the use of light to stimulate or inhibit neurons, has long held promise for revolutionizing the study and treatment
of neurological disorders caused by neuronal excitability that is too strong or too weak.
However, current optogenetic techniques can only alter the excitability
of neurons in the short term.
Once the light is extinguished, the neuron returns to its original behavior
.

Recent advances in nanotechnology, including flexible implantable nanoelectronics pioneered by Liu and his team, may alter the behavior of neurons in the long term, but these devices need to be implanted in the brain and cannot be programmed
to target specific neurons associated with disease.

The excitability of a neuron is determined by two main factors – its ion channel conductivity and the ability of the cell membrane to store charge, that is, its capacitance
.

Most optogenetic techniques target ion channel conductivity to modulate the excitability
of neurons by turning a specific set of channels on or off.
This approach can effectively modulate the excitability of neurons, but only temporarily
.

"You can think of a neuron as a resistive-capacitive circuit, and a cell membrane as a dielectric material," Jia Liu said
.
"Just like any circuit, if you change the capacitance of the material – in this case the cell membrane – you can change the intrinsic excitability of the circuit, from high excitability to low excitability and vice versa
.
"

To change the capacitance of the cell membrane, Liu teamed up with Xiao Wang, an assistant professor of chemistry at MIT, to use photoenzymes
that initiate the formation of insulating or conductive polymers on the surface of the cell membrane.

These enzymes can be designed to target the cell membranes
of specific neurons.
Once the enzyme attaches to a specific membrane, the researchers irradiate the neurons with blue wavelength light, triggering the formation
of an insulating or conductive coating on the membrane within minutes.
They showed that neurons with an insulating polymer coating became more excitable, while neurons with a conductive polymer coating became less easily excited
.

The researchers found that they could modulate excitability by adjusting the time of exposure to light — the longer neurons are exposed to light, the more insulating or conductive the coating
becomes.
The team also showed that as long as they kept neurons alive in the dish, the change in excitability lasted for three days
.

Next, the team intends to test this approach
with brain tissue sections and animal experiments.

"The overarching goal of this work is to achieve a paradigm shift approach that integrates functional materials, structures, and devices into living nervous systems with subcellular and cell type-specific, which will allow precise manipulation of subcellular electrochemical properties to remodel the excitability of neurons in living nervous systems"
.

The project was supported
in part by the Air Force Office of Scientific Research Young Investigators Program (FA9550-22-1-0228), the National Science Foundation (DMR-2011754) through the Harvard Center for Materials Research Science and Engineering (DMR-2011754), and the Harvard Dean's Promising Scholarship Competition Fund.

Journal Reference:

1. Chanan D.
   Sessler, Yiming Zhou, Wenbo Wang, Nolan D.
   Hartley, Zhanyan Fu, David Graykowski, Morgan Sheng, Xiao Wang, Jia Liu.
   Optogenetic polymerization and assembly of electrically functional polymers for modulation of single-neuron excitability.
   Science Advances, 2022; 8 (49) DOI: 10.
   1126/sciadv.
   ade1136