Northwestern Medicine investigators have uncovered new insights into the synaptic connections of subgroups of interneurons, findings that may improve the understanding of fear responses and could inform new targeted therapies for post-traumatic stress disorder (PTSD), according to a recent study published in Cell Reports.  

Sachin Patel, MD, PhD, the chair and the Lizzie Gilman Professor of Psychiatry and Behavioral Sciences, was senior author of the study.  

GABAergic interneurons (INs) are a specialized group of inhibitory neurons in the amygdala that support associative learning, a survival mechanism in which behavioral responses change to different environmental factors and sensory cues. GABAergic INs also help regulate excitatory neurons throughout the brain and central nervous system.  

There are thought to be three major types of GABAergic INs: somatostatin INs, vasoactive intestinal peptide (VIP) INs and parvalbumin (PV) INs. Each group expresses unique genetic signatures and functions differently within the brain’s cortex and amygdala, which play a role in fear conditioning and the development of post-traumatic stress disorder (PTSD).  

In the current study, Patel’s team aimed to better understand how these three specific groups of GABAergic INs adapt in response to fear induced by environmental stressors and during extinction, or when an environmental stressor is continually reinforced and the fear response gradually weakens over time due. 

“This is also important from a clinical perspective because it’s the basis of things like exposure therapy where patients are exposed to traumatic cues over and over again in a safe place with the hope that those conditioned responses will decrease over time,” Patel said. “Understanding how these GABAergic neurons are playing a role in this process in a coordinated way has never really been examined.”  

In transgenic mouse models, the scientists used electrophysiological analysis techniques to study the synaptic activity of each group of GABAergic INs while mice performed associative learning and extinction tasks.  

Specifically, they found that somatostatin INs mediate feedback inhibition and exhibit learning-induced plasticity changes during both associative learning and extinction tasks, while VIP INs mediate feedforward disinhibition and respond to salient sensory cues.  

“The somatostatin and the VIP INs really showed the most distinct differences in the way that they were connected to these principal neurons in the amygdala and in their responses during the acquisition of the associative learning task,” Patel said.  

The PV group, however, showed activity patterns similar to both somatostatin and VIP INs, participating in both feedback and feedforward inhibition.  

“The only way this was really able to be appreciated was to do a systematic analysis of all three types in all the experiments that we did, because previous studies that had looked at these genetically identified neurons had mostly looked at one group at a time,” Patel said.  

The scientists also found that when mice expressed “freezing” behavior, a measure of fear response, the activity of somatostatin INs decreased, whereas when they stopped showing this response, somatostatin IN activity increased.  

These findings improve the understanding of fear response and how GABAergic INs could be targeted to enhance the effectiveness of exposure therapy for patients with PTSD, Patel said.  

Patel said next steps for this work include manipulating the activity of each of group of GABAergic INs separately to determine which are most causally related to driving fear states as well as investigating other recently discovered groups of GABAergic INs in the amygdala.  

“As we start to understand how these different cell types are involved in regulating these fear behaviors as well as the learning process, it might give us an ultimate opportunity to then go in and figure out how might some treatment selectively activate those neurons, for example, to alleviate the fear state,” Patel said. 

Rita Báldi, PhD, a research associate in the Patel laboratory, was the first author of the study.  

This work was supported by National Institutes of Health grant MH11786 and a NARSAD Young Investigator Award.