ASD is a neurodevelopmental disorder characterized by impairments in social interactions and communication, as well as repetitive behaviours. Historically, ASD has been widely regarded as a disorder mainly affecting the male sex. An in-depth meta-analysis estimates the male-to-female ratio of ASD to be approximately 4:1, although this imbalance tends to be even higher (about 9:1) for individuals with normal or high IQ.
One approach to better understand the aetiology of ASD is to take candidate autism genes identified from human patients, generate mice (conditionally) mutant for these genes, and analyse functionally and structurally the neural circuits controlling, for example, social behaviours.
Our model system are mice mutant for the high confident ASD gene Cntnap2, a member of the neurexin family. Cntnap2 functions in the stabilization of synapses, like other members of the neurexin family.
We have shown in behavioural assays that only male – but not female - Cntnap2 KO mice show defects in social interactions (Dawson et al., 2023). These deficits in males can be rescued by treating these mice with drugs which suppress the activation of microglia, representing the main immune cells of the brain.
Thus broadly speaking, overactivation of microglia in response to defects in synapse development might contribute to the aetiology of ASD, in particular in males, while females might be less sensitive due to a postulated ‘female protective factor.’
To understand this sexually dimorphism in Cntnap2 KO mice, we are focussing on the anterior cingulate cortex (ACC) located in the medial prefrontal cortex, a prominent hub integrating neural circuits controlling social behaviour.
We are studying this area from early postnatal times to adult which enables us to detect (also) transient defects in circuit development. Here we found in male - but not female KO mice - a transient reduction in the density of dendritic spines of L2/3 and L5 pyramidal neurons in layer 1 of the ACC, possibly leading to the disruption of specific neural circuits, and behaviours controlled by these circuits.
Furthermore, only in male KO mice we observed activated microglia (based on their altered morphology), and which also showed an increased phagocytosis of synaptic structures when compared to WT male mice- and links directly to the reduced synapse densities. No differences were seen between female KO and WT mice (Dawson et al., 2023).
Our current analyses aim to understand the molecular signatures triggering the differential activation of microglia in male vs female KO mice. We investigate differences in the expression of the complement system, which tags synapses for microglial phagocytosis, as well as select interleukins and cytokines affecting microglia characteristics, and molecules which directly activate microglia. On the other hand, we analyse whether male and female microglia per se have different characteristics and therefore respond differentially to defects in the development of neural circuits.
Our long-term goal is the identification of biomarkers for an early detection of ASD.