Rachel June Smith, Ph.D., and Scott Cruikshank, Ph.D., have been selected for the FCIDD McNulty Civitan Scientist Award for 2025.

This award is given on behalf of the FCIDD McNulty Civitan Scientist Committee and the Civitan International Research Center which provides $75,000 per year for three years in funding for interdisciplinary clinical or fundamental science research aimed at enhancing understanding of typical and atypical brain development.

Their collaborative study will combine state-of-the-art electrophysiological recordings, optogenetic techniques, and computational analysis tools to better characterize the dysfunctional neuronal circuits associated with SLC6A1 neurodevelopmental disorders (NDDs).

Advancing discovery in SLC6A1 neurodevelopmental disorders

Rachel June Smith, Ph.D.The SLC6A1 is a gene that provides instructions to make a protein called GAT-1, which regulates levels of GABA, an inhibitory neurotransmitter that helps to control brain activity.

Mutations in this gene have been identified as a prominent monogenic cause of NDDs, which commonly present with epilepsy, autism spectrum disorder, intellectual disability, social impairments, and sleep disturbances.

Researchers, although familiar with SLC6A1-related NDDs, do not fully understand how the brain’s circuits are affected, resulting in a limitation in the development of effective treatments.

Smith, an assistant professor in the UAB School of Engineering Department of Electrical and Computer Engineering, is aiming to fill a major gap by understanding a specific part of the brain called the thalamic reticular nucleus (TRN), which plays a role in how SLC6A1-related NDDs develop.

“We hypothesize that mutations in SLC6A1 changes inhibitory activity of the TRN, and this disruption of physiological levels of inhibition causes reciprocal bursting between TRN and thalamocortical cells, giving rise to seizure-like activity,” said Smith.

“We believe that if we block receptors to bring back physiological levels of inhibition in these circuits, this may provide a potential strategy to rescue healthy activity in the thalamus.”

Smith will work closely with Cruikshank, an assistant professor in the UAB Heersink School of Medicine Department of Neurobiology, whose research examines how the brain processes signals at the cellular and circuit level.

Scott Cruikshank, Ph.D.“My past research has focused more on uncovering basic mechanisms of thalamocortical circuitry,” said Cruikshank. “I am thrilled to now have the opportunity to apply some of what we've learned from this basic science toward understanding SLC6A1 neurodevelopmental disorders.”

The researchers will test how partial loss of GAT-1 affects the brain’s ability to control signals in the thalamus, and whether this increases the likelihood of seizures. To do this, they will use two distinctive mouse models of SLC6A1-NDDs.

A mouse carrying a mutation found in real patients.

A mouse with the GAT-1 gene “turned off” by default, but that can be “turned back on” in specific brain cell types.

Using a high-resolution silicon probe, Smith and Cruikshank will probe two key areas in the brain—TRN and the somatosensory thalamocortical region (a group of cells that pass information from the thalamus to the cortex)—at the same time to record a high-resolution map of how brain signals move and interact.

To identify the specific cell types in these areas, the researchers will also use a previously established method from the Cruikshank Lab involving multicolor lasers. This will allow them to track how inhibitory signals from TRN cells affect thalamocortical cells.

At the final stage of their study, the researchers will test the effects of drug as a potential treatment, a drug which has already been tested for safety in humans, to see whether it can reduce seizures or normalize brain activity.

“There is a growing need to better understand the underlying circuit dysfunctions to develop more effective treatments for these patients, and the combination of unique expertise amongst our team will make these insights possible,” said Smith.