Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Ulk4 regulates GABAergic signaling and anxiety-related behavior. 2939 90

Diagnoses of behavioral disorders such as autism spectrum disorder and schizophrenia are based on symptomatic descriptions that have been difficult to connect to mechanism. Although psychiatric genetics provide insight into the genetic underpinning of such disorders, with a majority of cases explained by polygenic factors, it remains difficult to design rational treatments. In this review, we highlight the value of understanding neural circuit function both as an intermediate level of explanatory description that links gene to behavior and as a pathway for developing rational diagnostics and therapeutics for behavioral disorders. As neural circuits perform hierarchically organized computational functions and give rise to network-level processes (e.g., macroscopic rhythms and goal-directed or homeostatic behaviors), correlated network-level deficits may indicate perturbation of a specific circuit. Therefore, identifying such correlated deficits or a circuit endophenotype would provide a mechanistic point of entry, enhancing both diagnosis and treatment of a given behavioral disorder. We focus on a circuit endophenotype of the thalamic reticular nucleus (TRN) and how its impairment in neurodevelopmental disorders gives rise to a correlated set of readouts across sleep and attention. Because TRN neurons express several disorder-relevant genes identified through genome-wide association studies, exploring the consequences of different TRN disruptions may be of broad translational significance.
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PMID:Thalamic Reticular Dysfunction as a Circuit Endophenotype in Neurodevelopmental Disorders. 2967 80


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