Chronic inhibition of astrocytic aquaporin-4 induces autistic-like behavior in control rat offspring similar to maternal exposure to valproic acid.

Scientists studied a brain protein called AQP4 that helps control water balance in brain cells. When they blocked this protein in healthy young rats, the rats showed autism-like behaviors such as less social interaction, more anxiety, and memory problems - similar to rats whose mothers were exposed to a medication during pregnancy that causes autism-like traits. This suggests problems with brain water balance might contribute to autism symptoms.

This preclinical study investigated the role of aquaporin-4 (AQP4), a brain water channel protein, in autism-like behaviors using rat models. Researchers compared control rats treated with an AQP4 inhibitor (TGN-020) to rats exposed to valproic acid (VPA) prenatally, which typically induces autism-like behaviors. Results showed that inhibiting AQP4 in control rats produced behavioral changes similar to VPA-exposed rats, including reduced social interaction, increased anxiety, and impaired novel object recognition. Both groups showed increased water accumulation in the hippocampus.

The findings suggest AQP4 dysfunction may contribute to autism pathophysiology and could represent a potential therapeutic target.

While preliminary, this research identifies AQP4 as a potential target for autism interventions. However, extensive human studies are needed before clinical applications. The findings contribute to understanding of brain water regulation in autism.

Single animal study with unclear sample sizes and methodology. Findings may not translate to humans. Short-term behavioral assessment only. Mechanism of AQP4's role in autism behaviors remains unclear.

Social communication and interaction deficits, memory impairment, and anxiety-like behavior are characterized in many people identified with autism spectrum disorder (ASD). A thorough understanding of the specific aspects that contribute to the deficiencies associated with ASD can aid research into the etiology of the disorder while also providing targets for more effective intervention. As part of the ASD pathophysiology, alterations in synaptogenesis and abnormal network connections were seen in high-order brain areas, which control social behavior and communication. The early emergence of microglia during nervous system development may contribute to synaptic dysfunction and the pathobiology of ASD.

Since aquaporin-4 (AQP4) appears to be required for the basic procedures of synapse activation, certain behavioral and cognitive impairments as well as disturbance in water homeostasis might likely arise from AQP4 deficiency. Here, through the measurement of the water content of the hippocampus and behavioral experiments we aim to explore the contribution of astrocytic AQP4 to the autism-like behavior induced by prenatal valproic acid (VPA) exposure and whether inhibition of AQP4 per se can induce autistic-like behavior in control rats. Microinjection of TGN-020 (10 µM, i.c.v), a specific AQP4 inhibitor, for 7 successive days before behavioral tasks from postnatal day 28 to 35 revealed that inhibition of AQP4 in the control offspring caused lower social interaction and locomotor activity, higher anxiety, and decreased ability to recognize novel objects, very similar to the behavioral changes observed in offspring prenatally exposed to VPA. However, VPA-exposed offspring treated with TGN-020, showed no further remarkable behavioral impairments than those detected in the autistic-like rats.

Furthermore, both control offspring treated with TGN-020 and offspring exposed to VPA had a considerable accumulation of water in their hippocampi. But AQP4 inhibition did not affect the water status of the autistic-like rats. The findings of this study revealed that control offspring exhibited similar hippocampal water retention and behavioral impairments that were observed in maternal VPA-exposed offspring following inhibition of astrocytic AQP4, whereas, in autistic-like rats, it did not produce any significant change in water content and behaviors. Findings suggest that AQP4 deficiency could be associated with autistic disorder and may be a potential pharmaceutical target for treating autism in the future.