Molecular and behavioural abnormalities in the FUS-tg mice mimic frontotemporal lobar degeneration: Effects of old and new anti-inflammatory therapies.

Genetic mutations in FUS, a DNA/RNA-binding protein, are associated with inherited forms of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). A novel transgenic FUS[1-359]-tg mouse line recapitulates core hallmarks of human ALS in the spinal cord, including neuroinflammation and neurodegeneration, ensuing muscle atrophy and paralysis, as well as brain pathomorphological signs of FTLD. However, a question whether FUS[1-359]-tg mouse displays behavioural and brain pro-inflammatory changes characteristic for the FTLD syndrome was not addressed. Here, we studied emotional, social and cognitive behaviours, brain markers of inflammation and plasticity of pre-symptomatic FUS[1-359]-tg male mice, a potential FTLD model. These animals displayed aberrant behaviours and altered brain expression of inflammatory markers and related pathways that are reminiscent to the FTLD-like syndrome. FTLD-related behavioural and molecular Journal of Cellular and Molecular Medicine features were studied in the pre-symptomatic FUS[1-359]-tg mice that received standard or new ALS treatments, which have been reported to counteract the ALS-like syndrome in the mutants. We used anti-ALS drug riluzole (8 mg/kg/d), or anti-inflammatory drug, a selective blocker of cyclooxygenase-2 (celecoxib, 30 mg/kg/d) for 3 weeks, or a single intracerebroventricular (i.c.v.) infusion of human stem cells (Neuro-Cells, 500 000-CD34+ ), which showed anti-inflammatory properties. Signs of elevated anxiety, depressive-like behaviour, cognitive deficits and abnormal social behaviour were less marked in FUS-tg-treated animals. Applied treatments have normalized protein expression of interleukin-1ß (IL-1ß) in the prefrontal cortex and the hippocampus, and of Iba-1 and GSK-3ß in the hippocampus. Thus, the pre-symptomatic FUS[1-359]-tg mice demonstrate FTLD-like abnormalities that are attenuated by standard and new ALS treatments, including Neuro-Cell preparation.

Prefrontal cortex inflammation and liver pathologies accompany cognitive and motor deficits following Western diet consumption in non-obese female mice.

AIMS: The high sugar and lipid content of the Western diet (WD) is associated with metabolic dysfunction, non-alcoholic steatohepatitis, and it is an established risk factor for neuropsychiatric disorders. Our previous studies reported negative effects of the WD on rodent emotionality, impulsivity, and sociability in adulthood. Here, we investigated the effect of the WD on motor coordination, novelty recognition, and affective behavior in mice as well as molecular and cellular endpoints in brain and peripheral tissues. MAIN METHODS: Female C57BL/6 J mice were fed the WD for three weeks and were investigated for glucose tolerance, insulin resistance, liver steatosis, and changes in motor coordination, object recognition, and despair behavior in the swim test. Lipids and liver injury markers, including aspartate-transaminase, alanine-transaminase and urea were measured in blood. Serotonin transporter (SERT) expression, the density of Iba1-positive cells and concentration of malondialdehyde were measured in brain. KEY FINDINGS: WD-fed mice exhibited impaired glucose tolerance and insulin resistance, a loss of motor coordination, deficits in novel object exploration and recognition, increased helplessness, dyslipidemia, as well as signs of a non-alcoholic steatohepatitis (NASH)-like syndrome: liver steatosis and increased liver injury markers. Importantly, these changes were accompanied by decreased SERT expression, elevated numbers of microglia cells and malondialdehyde levels in, and restricted to, the prefrontal cortex. SIGNIFICANCE: The WD induces a spectrum of behaviors that are more reminiscent of ADHD and ASD than previously recognized and suggests that, in addition to the impairment of impulsivity and sociability, the consumption of a WD might be expected to exacerbate motor dysfunction that is also known to be associated with adult ADHD and ASD.