Ulk4 regulates GABAergic signaling and anxiety-related behavior

Excitation/inhibition imbalance has been proposed as a fundamental mechanism in the pathogenesis of neuropsychiatric and neurodevelopmental disorders, in which copy number variations of the Unc-51 like kinase 4 (ULK4) gene encoding a putative Serine/Threonine kinase have been reported in approximately 1/1000 of patients suffering pleiotropic clinical conditions of schizophrenia, depression, autistic spectrum disorder (ASD), developmental delay, language delay, intellectual disability, or behavioral disorder. The current study characterized behavior of heterozygous Ulk4(+/tm1a) mice, demonstrating that Ulk4(+/tm1a) mice displayed no schizophrenia-like behavior in acoustic startle reactivity and prepulse inhibition tests or depressive-like behavior in the Porsolt swim or tail suspension tests. However, Ulk4(+/tm1a) mice exhibited an anxiety-like behavioral phenotype in several tests. Previously identified hypo-anxious (Atp1a2, Ptn, and Mdk) and hyper-anxious (Gria1, Syngap1, and Npy2r) genes were found to be dysregulated accordingly in Ulk4 mutants. Ulk4 was found to be expressed in GABAergic neurons and the Gad67⁺ interneurons were significantly reduced in the hippocampus and basolateral amygdala of Ulk4(+/tm1a) mice. Transcriptome analyses revealed a marked reduction of GABAergic neuronal subtypes, including Pvalb, Sst, Cck, Npy, and Nos3, as well as significant upregulation of GABA receptors, including Gabra1, Gabra3, Gabra4, Gabra5, and Gabrb3. This is the first evidence that Ulk4 plays a major role in regulating GABAergic signaling and anxiety-like behavior, which may have implications for the development of novel anxiolytic treatments.