Can Overexpression of the EAAT3 Transporter Increase Susceptibility to Repetitive Behaviors?

What you need to know

• Mice genetically engineered to overexpress the EAAT3 glutamate transporter in the forebrain showed increased repetitive behaviors when given amphetamine.
• These repetitive behaviors were associated with increased activity in a specific region of the brain called the ventromedial striatum.
• The findings provide insight into how alterations in glutamate signaling may contribute to repetitive behaviors seen in conditions like obsessive-compulsive disorder (OCD).

Background on EAAT3 and OCD

Obsessive-compulsive disorder (OCD) is a mental health condition characterized by intrusive thoughts (obsessions) and repetitive behaviors (compulsions). While the exact causes are unknown, research has implicated both genetic and environmental factors. One gene that has been associated with OCD risk in humans is SLC1A1, which produces a protein called EAAT3.

EAAT3 is a transporter that moves the neurotransmitter glutamate from outside to inside of brain cells. Some genetic variations in SLC1A1 linked to OCD risk lead to increased production of EAAT3. To better understand how elevated EAAT3 levels might affect behavior, researchers created mice that produce extra EAAT3 in the forebrain - an area involved in complex behaviors.

Examining behavior in mice with extra EAAT3

The researchers conducted several experiments to assess the behavior of mice with elevated forebrain EAAT3 levels compared to control mice:

Baseline behaviors

When observed under normal conditions, the mice with extra EAAT3 did not show any major differences in anxiety-like behaviors or repetitive grooming compared to control mice. This suggests that simply having elevated EAAT3 is not sufficient to produce OCD-like behaviors.

Response to amphetamine

The key findings emerged when the mice were given amphetamine - a stimulant drug that increases dopamine signaling in the brain. At a low dose, mice with extra EAAT3 showed significantly more hyperactive locomotion (running around) than control mice. At a higher dose, they engaged in much more repetitive stereotyped behaviors like head bobbing.

This exaggerated response to amphetamine indicates that elevated EAAT3 makes the brain more sensitive to dopamine stimulation, leading to intensified repetitive behaviors. While not a direct model of OCD, this provides insight into how altered glutamate signaling could potentially increase susceptibility to repetitive behavior patterns.

Brain activity patterns

To understand the brain circuits involved, the researchers examined patterns of neuronal activation following amphetamine treatment:

Increased activity in ventral striatum

Mice with extra EAAT3 showed greater activation of neurons in a brain region called the ventral striatum, particularly in a subregion called the ventromedial striatum. This area is involved in motivation and reward processing.

Activation of D1 receptor neurons

The increased activity was specifically in neurons that express D1 dopamine receptors. These neurons tend to promote behavioral activation. The level of activity in these neurons correlated with the amount of repetitive behavior observed.

This suggests elevated EAAT3 may enhance the ability of dopamine to activate these D1 neurons in the ventral striatum, potentially driving repetitive behavioral output.

Novel analysis approach

An interesting aspect of this study was the use of machine learning to objectively analyze mouse behaviors. Rather than relying solely on human scoring, the researchers used an algorithm to categorize different behavior types based on body movements. This allowed for unbiased quantification of complex behavior patterns.

The machine learning analysis confirmed the human-observed findings of increased locomotion at low amphetamine doses and increased stereotypy at high doses in mice with extra EAAT3. It also revealed more nuanced differences in behavior sequences between the groups.

This demonstrates how advanced computational approaches can provide new insights in behavioral neuroscience research.

Relevance to OCD and related conditions

While this mouse study does not directly model OCD, it provides several insights relevant to understanding repetitive behavior disorders:

1. It shows how genetic variations that affect glutamate signaling could potentially increase susceptibility to developing repetitive behaviors.

2. It highlights interactions between glutamate and dopamine systems in driving repetitive behaviors - both neurotransmitters implicated in OCD.

3. It identifies the ventral striatum as a key brain region where altered glutamate transport affects behavioral responses.

4. The exaggerated response to amphetamine may relate to reports that stimulants can sometimes worsen OCD symptoms in humans.

Conclusions

• Increased levels of the glutamate transporter EAAT3 in the forebrain make mice more susceptible to repetitive behaviors induced by amphetamine.
• This behavioral effect is associated with increased activity in D1 receptor-expressing neurons in the ventral striatum.
• The findings provide new insight into how alterations in glutamate signaling could potentially contribute to repetitive behavior disorders like OCD.

While more research is needed to directly connect these findings to human OCD, this study adds to our understanding of the complex brain circuits involved in repetitive behaviors. It also demonstrates how genetic mouse models combined with advanced behavioral analysis techniques can shed light on the neurobiological basis of psychiatric symptoms.