How Does Lack of SAPAP3 Affect Brain Circuits and Behavior in Mice?

What you need to know

• Mice lacking the SAPAP3 protein show excessive grooming behavior starting in early adulthood, similar to compulsive behaviors in OCD.
• These mice have weakened connections between certain areas of the brain involved in movement control.
• The mice also move more slowly overall when exploring, suggesting broader effects on motor behavior.

Background on SAPAP3 and OCD

Obsessive-compulsive disorder (OCD) is a mental health condition characterized by persistent, intrusive thoughts (obsessions) and repetitive behaviors (compulsions). While the exact causes are not fully understood, research suggests OCD involves dysfunction in brain circuits connecting areas like the cortex and striatum, which are important for controlling behavior.

One protein that appears to play a role in these brain circuits is called SAPAP3. Some people with OCD have been found to have mutations in the gene for SAPAP3. To better understand how SAPAP3 affects brain function and behavior, researchers have studied mice that lack the Sapap3 gene. These “knockout” mice show behaviors similar to human OCD symptoms, like excessive grooming.

Excessive grooming starts early

Previous studies of Sapap3-knockout mice often focused on older animals, around 6 months of age, when they start to develop skin lesions from over-grooming. However, the researchers in this study wanted to examine behavior in younger adult mice, before any skin damage occurred.

They observed grooming behavior in Sapap3-knockout and normal mice between 7 and 25 weeks old. The knockout mice spent significantly more time grooming compared to normal mice, even at the youngest ages tested. Importantly, the amount of grooming did not increase with age during this period.

This suggests the compulsive-like grooming behavior in these mice emerges early in adulthood and remains relatively stable, rather than progressively worsening. The skin lesions seen in older mice may simply result from this persistent over-grooming over time.

Changes in brain circuit connections

To understand what might be causing the excessive grooming, the researchers examined connections between brain regions involved in controlling movement. They focused on synapses - the junctions where neurons communicate - between the cortex and striatum.

Using electrophysiology techniques in brain slices, they measured the strength of these synapses. In normal mice, activating cortical neurons produces a strong response in striatal neurons. However, this response was significantly weaker in the Sapap3-knockout mice.

Specifically, they found reduced signaling through a type of receptor called AMPA receptors, which are important for fast excitatory communication between neurons. This suggests the lack of SAPAP3 protein leads to fewer or less functional AMPA receptors at these synapses.

Interestingly, not all cortex-striatum connections were affected equally. The researchers saw these deficits in projections from the primary motor cortex to the dorsolateral striatum, and from the cingulate cortex to the dorsomedial striatum. However, connections from the orbitofrontal cortex to the central striatum appeared normal.

This selective pattern of synaptic changes may help explain why only certain behaviors, like grooming, are affected in these mice rather than all motor functions being disrupted.

Broader effects on movement

While excessive grooming was the most obvious behavioral change, the researchers also noticed the Sapap3-knockout mice moved differently overall. When placed in a novel open arena to explore, the knockout mice:

• Traveled less distance overall
• Spent less time moving
• Moved at slower speeds when they were mobile

This general slowness of movement, or hypolocomotion, was consistent across different ages tested. Importantly, it didn’t seem to be simply due to the mice stopping more often to groom. The number of pauses in movement was similar between knockout and normal mice.

To examine movement patterns in more detail, the researchers used an advanced video analysis technique called Motion Sequencing (MoSeq). This uses machine learning to automatically break down behavior into brief “syllables” of movement.

This analysis showed the Sapap3-knockout mice used more slow movement syllables and fewer fast movement syllables compared to normal mice. However, they didn’t show any unique movement patterns not seen in normal mice.

Implications for understanding OCD

These findings in mice may provide insights into how SAPAP3 mutations could contribute to OCD symptoms in humans. The weakened cortex-striatum connections align with other evidence that these circuits are disrupted in OCD. The early onset and persistence of compulsive-like grooming fits with OCD often emerging in adolescence or early adulthood.

The broader effects on movement speed are interesting, as some studies have found subtle motor slowing in people with OCD. However, it’s unclear if this is directly related to OCD symptoms or perhaps a side effect of the genetic changes. More research is needed to determine if people with SAPAP3 mutations show similar motor effects.

It’s important to note that while these mice show some OCD-like traits, they don’t capture all aspects of the human disorder. For example, we can’t assess mental obsessions or anxiety in mice. Animal models are useful tools for studying brain circuits and testing potential treatments, but findings don’t always translate directly to humans.

Conclusions

• Mice lacking SAPAP3 show excessive grooming starting in early adulthood, providing a model for studying compulsive behaviors.
• These mice have weakened connections between specific areas of the cortex and striatum involved in movement control.
• The mice also show an overall slowing of movement, suggesting broader effects of SAPAP3 loss on motor function.
• This research provides insights into how SAPAP3 mutations may contribute to circuit changes and symptoms in OCD.