Gabrd, encoding the δ subunit of extrasynaptic GABAA receptors, is involved in neurotransmission. It plays a crucial role in the GABAergic inhibitory neurotransmission system, which is essential for maintaining the balance of neural activity in the central nervous system [1,3].

In neurodevelopmental disorders and epilepsy, heterozygous missense GABRD variants were identified in patients. Electrophysiological measurements showed that five of seven variants altered the function of α1β3δ and α4β2δ GABAA receptors, with four causing gain-of-function and one loss-of-function. Patients with gain-of-function variants had common phenotypes like neurodevelopmental disorders, intellectual disability, and generalized epilepsy, while the patient with a loss-of-function variant had autism spectrum disorder and internalizing psychiatric symptoms [1].

In cancer research, GABRD has been associated with the progression of multiple cancers. In colorectal cancer, its expression is increased compared to adjacent normal tissues, and overexpression is related to later pTNM stages and poor patient survival. In esophageal squamous cell carcinoma (ESCC), it collaborates with DEPDC1B to regulate ESCC progression, and in gastric cancer, it accelerates tumour progression via regulating the CCND1 signalling pathway [2,4,5].

In addition, in a rat model, heroin self-administration led to GABRD gene hypomethylation and transcriptional upregulation in the nucleus accumbens, and manipulating GABRD expression affected heroin-seeking behavior [6].

In conclusion, Gabrd is vital for normal neural function, especially in neurotransmission. Its dysfunction, whether through genetic variants or altered expression, is linked to neurodevelopmental disorders, epilepsy, and various cancers. Studies on Gabrd, including those using relevant animal models, contribute to understanding the underlying mechanisms of these diseases and may provide new directions for treatment strategies.