How Does a Gene Linked to Autism Affect Brain Development and Behavior?

What you need to know

• The PCDH10 gene has been linked to autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD), and major depression in humans.
• This study in mice found that PCDH10 regulates the development of synapses (connections between neurons) in a key brain region called the amygdala.
• Mice lacking PCDH10 showed reduced anxiety and fear behaviors, suggesting this gene plays a role in regulating emotion.
• The findings provide insight into how genetic changes may contribute to neurodevelopmental and psychiatric disorders in humans.

How PCDH10 affects brain development

The PCDH10 gene provides instructions for making a protein called protocadherin-10. This protein is thought to play a role in the development of the nervous system, but its exact functions have been unclear. To investigate this, the researchers created mice that lacked a functional PCDH10 gene.

They found that PCDH10 is highly expressed in a part of the brain called the basolateral amygdala (BLA). The amygdala is involved in processing emotions, particularly fear and anxiety. Within the BLA, PCDH10 was most abundant in the dorsal region.

Importantly, mice lacking PCDH10 showed defects in the development of synapses in the dorsal BLA. Synapses are the junctions where neurons communicate with each other. Specifically, there was a decrease in excitatory synapses, which promote signaling between neurons.

This suggests that PCDH10 plays a critical role in forming proper connections between neurons in this emotion-processing region of the brain. Interestingly, the researchers did not find any defects in the growth or targeting of axons (the long projections that neurons use to send signals) in mice lacking PCDH10. This contradicts some previous studies and indicates that PCDH10’s main role is in synapse development rather than axon growth.

Effects on behavior

Given PCDH10’s effects on synapse development in the amygdala, the researchers next examined how lack of this gene impacted the mice’s behavior, particularly related to emotion and social interaction.

They found that mice lacking PCDH10 showed:

• Reduced anxiety-like behaviors in several tests
• Impaired fear conditioning (learning to associate a stimulus with a negative outcome)
• Decreased passive coping responses to stress
• Mild impairments in social recognition and communication

Importantly, the mice showed normal sensory and motor functions, indicating that the behavioral changes were not due to general deficits.

These behavioral changes align with PCDH10’s effects on synapse development in the amygdala. The dorsal BLA, where PCDH10 is most highly expressed, is known to be involved in processing negative emotions like fear and anxiety. The reduced anxiety and fear behaviors in mice lacking PCDH10 suggest that this gene normally acts to promote anxiety and fear responses.

Relevance to human disorders

The findings in mice provide insight into how PCDH10 may contribute to neurodevelopmental and psychiatric disorders in humans. Mutations in PCDH10 have been found in some individuals with ASD, and the gene has also been linked to OCD and major depression.

The mild social and communication deficits seen in mice lacking PCDH10 are reminiscent of features of ASD in humans. Additionally, anxiety and fear regulation are often impaired in ASD, OCD, and depression.

Interestingly, while the mice showed reduced anxiety, these disorders in humans are often characterized by increased anxiety. The researchers suggest this could mean that in humans, the mutations may lead to increased rather than decreased PCDH10 function. Alternatively, complete loss of PCDH10 (as in the mice) may have different effects than partial loss or altered function (as may occur in humans).

Potential clinical implications

Understanding PCDH10’s role in regulating synapses and emotional behaviors could potentially lead to new therapeutic approaches for disorders involving anxiety, fear, or social impairments. For example, the researchers suggest that inhibiting PCDH10 function could potentially help reduce excessive anxiety or fear in some conditions.

However, it’s important to note that findings in mice don’t always translate directly to humans. Much more research is needed to determine if and how targeting PCDH10 could be therapeutically useful in humans.

Conclusions

• The PCDH10 gene regulates the development of excitatory synapses in the amygdala, a brain region involved in processing emotions.
• Lack of PCDH10 in mice leads to reduced anxiety and fear behaviors, along with mild social recognition and communication deficits.
• These findings provide insight into how PCDH10 mutations may contribute to neurodevelopmental and psychiatric disorders in humans.
• Further research is needed to determine if targeting PCDH10 function could have therapeutic potential for anxiety or social impairments in humans.

This study highlights the complex relationship between genes, brain development, and behavior. It demonstrates how alterations in a single gene can have widespread effects on neural circuits and, consequently, behavior. As we continue to unravel these relationships, we may gain new insights into the biological underpinnings of complex disorders like ASD, OCD, and depression, potentially leading to novel treatment approaches in the future.