U of A study sheds new light on how GABA affects nervous system

NMHI members Dave Bennett and Monica Gorassini

Neuroscientists at the University of Alberta have discovered that one of the major chemical messengers that allow our nerves to function doesn’t work the way we previously thought. The finding not only changes our understanding of how the brain and nervous system function but could have implications for how drugs are prescribed to treat certain conditions.

Our nervous system is a complex network of nerve cells that sends signals back and forth and allows the body to react, think and move within our environments. It has long been believed that one of the signals, gamma-aminobutyric acid (GABA) blocks nerve signals and thereby decreases the communication between neurons. 

However, there is one problem: GABA is also known to excite the cables (axons) of some nerve cells in the brain. For many years it was thought this excitation actually suppressed information flow from the endings of sensory nerves in the spinal cord, even though it made axons in the brain more excitable. It is this contradiction and an unproven assumption about the fidelity of sensory axon conduction that the U of A team sought to address. 

“There are two long-standing inconsistencies in our understanding of neuron function, which we felt may point to fundamental flaws in our general ideas of how the brain and spinal cord function,” says neuroscience professor and Neuroscience and Mental Health Institute (NMHI) member Dave Bennett. 

“First, while GABA is considered the major inhibitory neurotransmitter in the brain, it paradoxically excites some neurons, including sensory axons in the adult spinal cord. Second, while axons are considered to conduct signals faithfully from the neuron cell body to target neurons, indirect experiments have suggested this is often not the case, though this has never been directly observed.” 

Bennett’s research team set out to show two things: that axons often fail to conduct signals, especially when they travel past complex branch points, and that GABA actually helps prevent this failure. 

Students Krista Metz, Krishnapriya (Veni) Hari and Yaqing (Celia) Li and adjunct professor in rehabilitation medicine Ana Lucas Osma contributed to this study.

“We did this by using genetically engineered mice to release GABA onto axons in response to laser light applied to the spinal cord, and then showed that light increased sensory feedback to muscles of mice,” says Bennett. “This shows that GABA increases the function of muscles, rather than inhibits them.”

Bennett also teamed up with the laboratories of three other NMHI researchers —  Kelvin Jones, Keith Fenrich and Monica Gorassini — to use mathematical models of the sensory axon and in vivo animal and human experiments to verify and translate these findings. These results represent a fundamental shift in the understanding of GABA: it has an excitatory action on sensory axons and regulates which axon branches conduct signals and which fail to conduct, acting like a router in a network. The findings were published in the prestigious journal Nature Neuroscience. 

Outside of improving the understanding of how our brain and nerves function, the discovery of excitatory actions of GABA suggests that many clinically used drugs that activate GABA receptors may have unexpected or undesirable actions on nerve cells, perhaps promoting excess sensory transmission and muscle spasms in conditions like spinal cord injury.  

The next steps for the team involve investigating whether drugs or genetic approaches that turn down excessive GABA receptor activity after spinal cord injury might reduce muscle spasms and improve recovery of function after injury.