Have you ever felt your knees shake and your hands sweating? Well, that may very well be your experience of the common symptoms of anxiety. Anxiety is driven by overactive neurons in the amygdala, and imbalances in neurotransmitters like serotonin and GABA. These may seem like big words, but to put it simply, an overactive amygdala refers to a condition in which the amygdala, which is part of the brain’s limbic system responsible for processing emotions and fear responses, becomes excessively reactive. This can lead to heightened emotional reactions and increased anxiety levels.
But fear no more, as a recent neuroscientific study at the Institute for Neurosciences (IN), led by Juan Lerma, has found that by rebalancing the activity of amygdalas in mice, the exaggerated effects have been reversed. The work entails a precise neural mechanism that could lead to more localized treatments for mood disorders.
“We already knew the amygdala was involved in anxiety and fear, but now we’ve identified a specific population of neurons whose imbalanced activity alone is sufficient to trigger pathological behaviors,” explains Lerma. His team worked with a genetically engineered mouse line that produces too much of Grik4, a gene that encodes a subunit of the kainate receptor. The kainate receptor is a type of ionotropic glutamate receptor in the central nervous system which is crucial for excitatory neurotransmission and synaptic plasticity. The Grik4 gene is also involved in functions related to learning, memory, and mood regulation.
Too much of the Grik4 gene boosts levels of GluK4 glutamate receptors, which fundamentally makes neurons overly excitable. The same lab created these mice in 2015, and they show both strong anxiety and social withdrawal behaviors reminiscent of symptoms in autism or schizophrenia.
The researchers then selectively lowered Grik4 activity only in neurons of the basolateral amygdala. In doing so, they restored normal signaling with a set of regular-spiking inhibitory neurons in the centrolateral amygdala. “That one targeted correction was enough to eliminate the anxiety-like and social problems, which is astonishing,” says first author Álvaro García.
To study these effects, the team used electrophysiology and a battery of behavioral tests for anxiety, depression, and social interaction, such as measuring whether mice prefer open vs. enclosed spaces or whether they approach unfamiliar mice. With genetic tools and modified viruses, they were able to fix the amygdala-specific malfunction and monitored how neuronal firing and behavior changed.
They applied the same intervention to wild-type mice that naturally show high anxiety, and the treatment reduced their anxiety as well. “This reinforces our conclusions and suggests that the mechanism we found is not limited to a single genetic model but may reflect a broader rule for how these emotions are controlled in the brain,” Lerma explains.
However, some cognitive problems, like impaired object-recognition memory, did not improve, indicating that other areas such as the hippocampus also contribute. Even so, the findings point to promising therapeutic directions. “Focusing on these specific neural circuits could offer a more precise and effective way to treat affective disorders,” Lerma says. Can you imagine a life without anxiety?