Advances toward precision therapeutics for developmental and epileptic encephalopathies

Developmental and epileptic encephalopathies are childhood syndromes of severe epilepsy associated with cognitive and behavioral disorders. Of note, epileptic seizures represent only a part, although substantial, of the clinical spectrum. Whether the epileptiform activity per se accounts for developmental and intellectual disabilities is still unclear. In a few cases, seizures can be alleviated by antiseizure medication (ASM). However, the major comorbid features associated remain unsolved, including psychiatric disorders such as autism-like and attention deficit hyperactivity disorder-like behavior. Not surprisingly, the number of genes known to be involved is continuously growing, and genetically engineered rodent models are valuable tools for investigating the impact of gene mutations on local and distributed brain circuits. Despite the inconsistencies and problems arising in the generation and validation of the different preclinical models, those are unique and precious tools to identify new molecular targets, and essential to provide prospects for effective therapeutics

Advances toward precision therapeutics for developmental and epileptic encephalopathies

Developmental and epileptic encephalopathies are childhood syndromes of severe epilepsy associated with cognitive and behavioral disorders. Of note, epileptic seizures represent only a part, although substantial, of the clinical spectrum. Whether the epileptiform activity per se accounts for developmental and intellectual disabilities is still unclear. In a few cases, seizures can be alleviated by antiseizure medication (ASM). However, the major comorbid features associated remain unsolved, including psychiatric disorders such as autism-like and attention deficit hyperactivity disorder-like behavior. Not surprisingly, the number of genes known to be involved is continuously growing, and genetically engineered rodent models are valuable tools for investigating the impact of gene mutations on local and distributed brain circuits. Despite the inconsistencies and problems arising in the generation and validation of the different preclinical models, those are unique and precious tools to identify new molecular targets, and essential to provide prospects for effective therapeutics

Distinct effects of AMPA receptor subunit depletion on spatial memory

Pharmacological studies established a role for AMPARs in the mammalian forebrain in spatial memory performance. Here we generated global GluA1/3 double knockout mice (Gria1/3−/−) and conditional knockouts lacking GluA1 and GluA3 AMPAR subunits specifically from principal cells across the forebrain (Gria1/3ΔFb). In both models, loss of GluA1 and GluA3 resulted in reduced hippocampal GluA2 and increased levels of the NMDAR subunit GluN2A. Electrically-evoked AMPAR-mediated EPSPs were greatly diminished, and there was an absence of tetanus-induced LTP. Gria1/3−/− mice showed premature mortality. Gria1/3ΔFb mice were viable, and their memory performance could be analyzed. In the Morris water maze (MWM), Gria1/3ΔFb mice showed profound long-term memory deficits, in marked contrast to the normal MWM learning previously seen in single Gria1−/− and Gria3−/− knockout mice. Our results suggest a redundancy of function within the pool of available ionotropic glutamate receptors for long-term spatial memory performance

Conditional Inactivation of Limbic Neuropeptide Y-1 Receptors Increases Vulnerability to Diet-Induced Obesity in Male Mice

NPY and its Y1 cognate receptor (Y1R) have been shown to be involved in the regulation of stress, anxiety, depression and energy homeostasis. We previously demonstrated that conditional knockout of Npy1r gene in the excitatory neurons of the forebrain of adolescent male mice (Npy1rrfb mice) decreased body weight growth and adipose tissue and increased anxiety. In the present study, we used the same conditional system to examine whether the targeted disruption of the Npy1r gene in limbic areas might affect susceptibility to obesity and associated disorders during adulthood in response to a 3-week high-fat diet (HFD) regimen. We demonstrated that following HFD exposure, Npy1rrfb male mice showed increased body weight, visceral adipose tissue, and blood glucose levels, hyperphagia and a dysregulation of calory intake as compared to control Npy1r2lox mice. These results suggest that low expression of Npy1r in limbic areas impairs habituation to high caloric food and causes high susceptibility to diet-induced obesity and glucose intolerance in male mice, uncovering a specific contribution of the limbic Npy1r gene in the dysregulation of the eating/satiety balance

Short- and long-term effects of essential oils on swine spermatozoa during liquid phase refrigeration

: The application of essential oils as potential alternatives to antibiotics in swine semen storage is promising, due to their antioxidant and antibacterial properties. However, detrimental effects on spermatozoa should be clarified first. The aim of this study was to evaluate 9 essential oils (EOs; Satureja montana, Pelargonium graveolens, Cymbopogon nardus, Melaleuca leucadendron, Eucaliptus globulus, Citrus limon, Lavandula angustifolia, Lavandula hybrida, Mentha piperita) and a blend (GL mix) on key morpho-functional parameters of swine spermatozoa. Test compounds were firstly chemo-characterized and experimental doses were prepared by suspending a fixed number of spermatozoa with 3 different concentrations (0.1, 0.5, 1 mg/mL) of EOs. Experimental doses were stored at 16 °C and sampled after 3 and 120 h for analysis. Overall, S. montana, P. graveolens and L. angustifolia EOs induced the strongest alterations, with C. nardus and E. globulus EOs being the best tolerated. Swine spermatozoa represent a good preliminary testing platform to screen toxicity and its different patterns. The comprehensive overview on the potential mechanisms of action of some of the most common EOs, despite of the direct aim of the study being swine reproduction, may be exploited in other fields of research within both veterinary and human medicine