In vivo Perturb-seq identifies Dennd1a as a key MDD risk gene impairing oxytocin signaling

Major depressive disorder (MDD) is a highly complex psychiatric condition, with numerous genetic risk factors identified through genome-wide association studies (GWAS). However, the precise in vivo functions of these risk genes and how they contribute to MDD pathophysiology remain largely unknown. Current treatments for MDD often lack specificity and efficacy for all patients, highlighting a critical need for a deeper understanding of underlying molecular mechanisms to develop more targeted and effective therapeutic strategies. This study addresses this gap by investigating the functional impact of MDD risk genes on brain transcriptional features.

Researchers developed an innovative in vivo adeno-associated virus (AAV)-Perturb-seq system to conduct parallel loss-of-function screening of MDD risk genes directly within the mouse brain. This system allowed for the systematic definition of their transcriptional effects and functional relationships. Perturbation profiles from these mouse models were then rigorously compared with existing transcriptomic data obtained from human patients diagnosed with MDD. As a specific example, mechanistic studies focused on the gene Dennd1a, investigating its neuron-specific downregulation and the subsequent impact on cellular pathways and behavior. The study also explored the effects of pharmacological enhancement of the identified pathway.

The AAV-Perturb-seq screening successfully identified a distinct cluster of MDD risk genes whose loss-of-function led to a significant neuronal downregulation of oxytocin signaling. Crucially, this specific transcriptional feature was found to be shared with transcriptomic data from human patients with MDD, establishing a direct translational link. Mechanistic investigations, using Dennd1a as a prime example, revealed that its neuron-specific downregulation directly impaired the oxytocin receptor-extracellular signal-regulated kinase (ERK) pathway. This impairment subsequently induced clear depressive-like behaviors in the mouse models. The study further demonstrated the therapeutic potential of targeting this pathway: > Pharmacological enhancement of the oxytocin receptor-ERK pathway successfully alleviated these depressive-like phenotypes in Dennd1a-deficient mice. This intervention also effectively restored oxytocin signaling in DENND1A-deficient human neurons, providing strong evidence for the pathway's critical role and its potential as a therapeutic target.