Abstract
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.
Highlights
Anxiety disorders are a category of mental disorders, including generalized anxiety disorder, panic disorder and phobias, characterized by feelings of anxiety and fear
We demonstrated that the Ulk4+/tm1a mice exhibited anxietyrelated phenotype, with no significant alteration in schizophrenia-related behavior such as prepulse inhibition (PPI), acoustic startle reactivity (ASR), or depressionlike behavior of Porsolt swim test (PST) and tail suspension test (TST)
Ulk4+/tm1a male mice exhibit impaired social novelty preference Ulk4+/tm1a mice were comprehensively examined for behavioral changes, as single-copy deletion of the ULK4 gene was identified in patients of neuropsychiatric and neurodevelopmental disorders[7,8]
Summary
Anxiety disorders are a category of mental disorders, including generalized anxiety disorder, panic disorder and phobias, characterized by feelings of anxiety and fear. They are the most common mental illness with an estimated prevalence of approximately 20% of world population, affecting 69 million of people in the EU1. A meta-analysis was carried out and showed that deletions of hypo-anxious genes were accompanied with increased anxiety, whereas deletions of other hyper-. Anxious genes were shown to result in decreased anxiety, with both presynaptic and postsynaptic genes involved[2]. Clinical evidence suggests that altered GABA transmission contributes to the pathophysiology of anxiety disorders in humans. The levels of circulating GABA in the central nervous system is largely determined by the Gad67+ cells, as deletion of the Gad[1] gene results in >90% reduction in basal GABA levels, whereas Gad2−/− mice expressed normal levels of GABA5,6
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