Bate palmas mutant mice as a model of Kabuki syndrome: Higher susceptibility to infections and vocalization impairments?

The recessive mutant mouse bate palmas (bapa) arose from N-ethyl-N-nitrosourea mutagenesis. Previous studies of our group revealed some behavioral impairments and a mutation in the lysine (K)-specific methyltransferase 2D (Kmt2d) gene. Because mutations in the KMT2D gene in humans are mainly responsible for Kabuki syndrome, this study was proposed to validate bapa mice as a model of Kabuki syndrome. Besides other symptoms, Kabuki syndrome is characterized by increased susceptibility to infections and speech impairments, usually diagnosed in the early childhood. Thus, juvenile male and female bapa mice were studied in different developmental stages (prepubertal period and puberty). To induce sickness behavior and to study infection susceptibility responses, lipopolysaccharide (LPS) was used. To study oral communication, ultrasonic vocalizations were evaluated. Behavioral (open-field test) and central (astrocytic glial fibrillary acidic protein [GFAP] and tyrosine hydroxylase [TH]) evaluations were also performed. Control and bapa female mice emitted 31-kHz ultrasounds on prepubertal period when exploring a novel environment, a frequency not yet described for mice, being defined as 31-kHz exploratory vocalizations. Males, LPS, and puberty inhibited these vocalizations. Bapa mice presented increased motor/exploratory behaviors on prepubertal period due to increased striatal TH expression, revealing striatal dopaminergic system hyperactivity. Combining open-field behavior and GFAP expression, bapa mice did not develop LPS tolerance, that is, they remained expressing signs of sickness behavior after LPS challenge, being more susceptible to infectious/inflammatory processes. It was concluded that bapa mice is a robust experimental model of Kabuki syndrome.

Induction of Type 2 Iodothyronine Deiodinase After Status Epilepticus Modifies Hippocampal Gene Expression in Male Mice.

Status epilepticus (SE) is an abnormally prolonged seizure that results from either a failure of mechanisms that terminate seizures or from initiating mechanisms that inherently lead to prolonged seizures. Here we report that mice experiencing a 3 hours of SE caused by pilocarpine exhibit a rapid increase in expression of type 2 iodothyronine deiodinase gene (Dio2) and a decrease in the expression of type 3 iodothyronine deiodinase gene in hippocampus, amygdala and prefrontal cortex. Type 3 iodothyronine deiodinase in hippocampal sections was seen concentrated in the neuronal nuclei, typical of ischemic injury of the brain. An unbiased analysis of the hippocampal transcriptome of mice undergoing 3 hours of SE revealed a number of genes, including those involved with response to oxidative stress, cellular homeostasis, cell signaling, and mitochondrial structure. In contrast, in mice with targeted disruption of Dio2 in astrocytes (Astro D2KO mouse), the highly induced genes in the hippocampus were related to inflammation, apoptosis, and cell death. We propose that Dio2 induction caused by SE accelerates production of T3 in different areas of the central nervous system and modifies the hippocampal gene expression profile, affecting the balance between adaptive and maladaptive mechanisms.