Ulk4 regulates GABAergic signaling and anxiety-related behavior

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.

Panic results in unique molecular and network changes in the amygdala that facilitate fear responses

“…Here, we have observed network, gene, and protein changes in the BLA that confirm a coherent pattern of synaptic physiology and result in diminished GABA synaptic transmission and enhanced glutamate neurotransmission. Our data is in agreement with previous reports that showed correlation between anxiety and fear and either reduced number of GABAergic interneurons 58 or GABAergic inhibition in the BLA 59 – 62 . The network changes we have described in the BLA were associated with a significant reduction in local expression of the mGluR2 receptor protein, consistent with reduced presynaptic inhibition of glutamate release.…”

Nucleotide Binding, Evolutionary Insights, and Interaction Partners of the Pseudokinase Unc-51-like Kinase 4

“…Deletion of ULK4 in mice results in hydrocephalus, a condition linked to impaired cilia development (Vogel et al, 2012). Multiple roles for ULK4 in brain development and neuronal function have been reported, including neuronal motility (Lang et al, 2014), cortex development (Lang et al, 2016), hypomyelination (Liu et al, 2018b), and GABAergic signaling (Liu et al, 2018a). However, a molecular mechanism of how ULK4 mediates these cellular signaling functions is lacking.…”

Ulk4, a Newly Discovered Susceptibility Gene for Schizophrenia, Regulates Corticogenesis in Mice

“…Detailed molecular pathways are yet to be established, but Ulk4 hypomorph mice displayed dysregulated inhibitory circuits ( Liu et al, 2018a ) and reduced white matter integrity ( Liu et al, 2018b ), the two most frequent phenotypes that predispose mental disorders and neurodevelopmental diseases ( Lewis et al, 2005 ; Peters and Karlsgodt, 2015 ). Unbalanced Wnt signaling is another promising candidate that links the two categories of diseases.…”