Cholinergic neurons in the basal forebrain are involved in behavioral abnormalities associated with Cul3 deficiency: Role of prefrontal cortex projections in cognitive deficits.

Loss-of-function mutations of the gene Cul3 have been identified as a risk factor for autism-spectrum disorder (ASD), but the pathogenic mechanisms are not well understood. Conditional Cul3 ablation in cholinergic neurons of mice (ChatCul3) recapitulated ASD-like social and sensory gating phenotypes and caused significant cognitive impairments, with diminished activity of cholinergic neurons in the basal forebrain (BF). Chemogenetic inhibition of BF cholinergic neurons in healthy mice induced similar social and cognitive deficits.

White matter abnormalities in the knockout mouse, a model of tic and OCD pathophysiology.

Introduction: An inactivating mutation in the gene () has been identified as a rare but high-penetrance genetic cause of Tourette syndrome (TS). TS is a neurodevelopmental syndrome characterized by recurrent motor and vocal tics; it is accompanied by structural and functional abnormalities in the cortico-basal ganglia circuitry. , which is expressed both in the posterior hypothalamus and peripherally, encodes an enzyme required for the biosynthesis of histamine.

Targeting histone demethylase LSD1 for treatment of deficits in autism mouse models.

Large-scale genetic studies have revealed that the most prominent genes disrupted in autism are chromatin regulators mediating histone methylation/demethylation, suggesting the central role of epigenetic dysfunction in this disorder. Here, we show that histone lysine 4 dimethylation (H3K4me2), a histone mark linked to gene activation, is significantly decreased in the prefrontal cortex (PFC) of autistic human patients and mutant mice with the deficiency of top-ranking autism risk factor Shank3 or Cul3. A brief treatment of the autism models with highly potent and selective inhibitors of the H3K4me2 demethylase LSD1 (KDM1A) leads to the robust rescue of core symptoms of autism, including social deficits and repetitive behaviors.

Behavioral, circuitry, and molecular aberrations by region-specific deficiency of the high-risk autism gene Cul3.

Cullin 3 (Cul3) gene, which encodes a core component of the E3 ubiquitin ligase complex that mediates proteasomal degradation, has been identified as a true high-risk factor for autism. Here, by combining behavioral, electrophysiological, and proteomic approaches, we have examined how Cul3 deficiency contributes to the etiology of different aspects of autism. Heterozygous mice with forebrain Cul3 deletion displayed autism-like social interaction impairment and sensory-gating deficiency.

Striatal Signaling Regulated by the H3R Histamine Receptor in a Mouse Model of tic Pathophysiology.

Histamine dysregulation has been identified as a rare genetic cause of tic disorders; mice with a knockout of the histidine decarboxylase (Hdc) gene represent a promising model of this pathophysiology. How alterations in the histamine system lead to neuropsychiatric disease, however, remains unclear. The H3R histamine receptor is elevated in the striatum of Hdc KO mice, and H3R agonists, acting in the dorsal striatum, trigger tic-like movements in the model.