Delayed Outgrowth in Response to the BDNF and Altered Synaptic Proteins in Neurons From SHR Rats.

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity, and impulsivity symptoms. Neuroimaging studies have revealed a delayed cortical and subcortical development pattern in children diagnosed with ADHD. This study followed up on the development in vitro of frontal cortical neurons from Spontaneously hypertensive rats (SHR), an ADHD rat model, and Wistar-Kyoto rats (WKY), control strain, over their time in culture, and in response to BDNF treatment at two different days in vitro (DIV). These neurons were also evaluated for synaptic proteins, brain-derived neurotrophic factor (BDNF), and related protein levels. Frontal cortical neurons from the ADHD rat model exhibited shorter dendrites and less dendritic branching over their time in culture. While pro- and mature BDNF levels were not altered, the cAMP-response element-binding (CREB) decreased at 1 DIV and SNAP-25 decreased at 5 DIV. Different from control cultures, exogenous BDNF promoted less dendritic branching in neurons from the ADHD model. Our data revealed that neurons from the ADHD model showed decreased levels of an important transcription factor at the beginning of their development, and their delayed outgrowth and maturation had consequences in the levels of SNAP-25 and may be associated with less response to BDNF. These findings provide an alternative tool for studies on synaptic dysfunctions in ADHD. They may also offer a valuable tool for investigating drug effects and new treatment opportunities.

Sex differences in maternal odor preferences and brain levels of GAP-43 and sonic hedgehog proteins in infant SHR and Wistar Kyoto rats.

Attention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder that presents sex differences in the severity and presentation of symptoms, whose neurobiological basis is still unknown. Both Growth-associated Protein 43 (GAP-43) and Sonic hedgehog (Shh) are considered essential proteins for the appropriate brain development, but their participation in ADHD neurobiology have not been investigated yet. In this study, we hypothesized that alterations in these proteins could be related to behavioral traits to ADHD phenotype. Thus, both sexes of infant Spontaneously hypertensive rats (SHR, used as ADHD animal model) were evaluated for developmental milestones, locomotor activity, olfactory and recognition memory. Both GAP-43 and Shh were assessed in the olfactory bulb, frontal cortex and hippocampus in early and late infancy. During early infancy, SHR reached three developmental milestones later, and females showed olfactory memory impairment accompanied by increased levels of Shh in the olfactory bulb. In later infancy, hyperlocomotion, impaired recognition memory, and decreased Shh in the hippocampus were observed in SHR from both sexes. While in early infancy GAP-43 was not altered, it was decreased in the frontal cortex and hippocampus of female SHR in late infancy. Therefore, both Shh and GAP-43 are involved in the sex-dependent behavioral alterations showed by infant SHR. Despite the disorder's complexity and heterogeneity, our findings reveal important developmental parameters during SHR development and also emphasizes the relevance of studying sex differences in the ADHD context.

Caffeine and adenosine A2A receptors rescue neuronal development in vitro of frontal cortical neurons in a rat model of attention deficit and hyperactivity disorder.

Although some studies have supported the effects of caffeine for treatment of Attention deficit and hyperactivity disorder (ADHD), there were no evidences about its effects at the neuronal level. In this study, we sought to find morphological alterations during in vitro development of frontal cortical neurons from Spontaneoulsy hypertensive rats (SHR, an ADHD rat model) and Wistar-Kyoto rats (WKY, control strain). Further, we investigated the effects of caffeine and adenosine A1 and A2A receptors (A1R and A2AR) signaling. Cultured cortical neurons from WKY and SHR were analyzed by immunostaining of microtubule-associated protein 2 (MAP-2) and tau protein after treatment with either caffeine, or A1R and A2AR agonists or antagonists. Besides, the involvement of PI3K and not PKA signaling was also assessed. Neurons from ADHD model displayed less neurite branching, shorter maximal neurite length and decreased axonal outgrowth. While caffeine recovered neurite branching and elongation from ADHD neurons via both PKA and PI3K signaling, A2AR agonist (CGS 21680) promoted more neurite branching via PKA signaling. The selective A2AR antagonist (SCH 58261) was efficient in recovering axonal outgrowth from ADHD neurons through PI3K and not PKA signaling. For the first time, frontal cortical neurons were isolated from ADHD model and they presented disturbances in the differentiation and outgrowth. By showing that caffeine and A2AR may act at neuronal level rescuing ADHD neurons outgrowth, our findings strengthen the potential of caffeine and A2AR receptors as an adjuvant for ADHD treatment.

Blood-feeding induces reversible functional changes in flight muscle mitochondria of Aedes aegypti mosquito.

BACKGROUND: Hematophagy poses a challenge to blood-feeding organisms since products of blood digestion can exert cellular deleterious effects. Mitochondria perform multiple roles in cell biology acting as the site of aerobic energy-transducing pathways, and also an important source of reactive oxygen species (ROS), modulating redox metabolism. Therefore, regulation of mitochondrial function should be relevant for hematophagous arthropods. Here, we investigated the effects of blood-feeding on flight muscle (FM) mitochondria from the mosquito Aedes aegypti, a vector of dengue and yellow fever. METHODOLOGY/PRINCIPAL FINDINGS: Blood-feeding caused a reversible reduction in mitochondrial oxygen consumption, an event that was parallel to blood digestion. These changes were most intense at 24 h after blood meal (ABM), the peak of blood digestion, when oxygen consumption was inhibited by 68%. Cytochromes c and a+a(3) levels and cytochrome c oxidase activity of the electron transport chain were all reduced at 24 h ABM. Ultrastructural and molecular analyses of FM revealed that mitochondria fuse upon blood meal, a condition related to reduced ROS generation. Consistently, BF induced a reversible decrease in mitochondrial H(2)O(2) formation during blood digestion, reaching their lowest values at 24 h ABM where a reduction of 51% was observed. CONCLUSION: Blood-feeding triggers functional and structural changes in hematophagous insect mitochondria, which may represent an important adaptation to blood feeding.