Neuroscience
-
Mice lacking the homeodomain transcription factor Engrailed-2 (En2(-/-) mice) are a well-characterized model for autism spectrum disorders (ASD). En2(-/-) mice present molecular, neuropathological and behavioral deficits related to ASD, including down-regulation of ASD-associated genes, cerebellar hypoplasia, interneuron loss, enhanced seizure susceptibility, decreased sociability and impaired cognition. Specifically, impaired spatial learning in the Morris water maze (MWM) is associated with reduced expression of neurofibromin and increased phosphorylation of extracellular-regulated kinase (ERK) in the hippocampus of En2(-/-) adult mice. ⋯ Here we show that SynI mRNA and protein levels are down-regulated in the hippocampus of naïve and MWM-treated En2(-/-) mice, as compared to WT controls. This down-regulation is paralleled by reduced levels of SynI phosphorylation at Ser549 and Ser553 residues in the hilus of mutant mice, before and after MWM. These data indicate that in En2(-/-) hippocampus, neurofibromin-dependent pathways converging on SynI phosphorylation might underlie hippocampal-dependent learning deficits observed in En2(-/-) mice.
-
Polycytosine-binding proteins (PCBPs) are RNA-binding proteins that participate in post-transcriptional control pathways. Among the diverse functions of these proteins is the interaction with a 27 nucleotide pyrimidine-rich domain within the 3'UTR of tyrosine hydroxylase (TH) mRNA. Mutations to this domain result in decreased stability of TH mRNA and loss of cAMP-mediated activation of TH mRNA translation. ⋯ Fluorescent immunohistochemistry and confocal microscopy was used to analyze the distribution of PCBP isoforms in TH-positive cells of the rat midbrain, locus coeruleus, and adrenal gland. Our results suggest that: (1) PCBP2 is the predominant isoform in TH-positive cells of the rat midbrain; (2) PCBP3 is the predominant isoform in TH-positive cells of the locus coeruleus; and (3) PCBP1 is the predominant isoform in the adrenal medulla. The localization of PCBP proteins to TH-positive cells in these catecholaminergic tissues is consistent with the hypothesis that PCBPs play a role in the regulation of TH expression.
-
A large body of evidence indicates that individual differences in baseline concentrations of testosterone (T) are only weakly correlated with human aggression. Importantly, T concentrations are not static, but rather fluctuate rapidly in the context of competitive interactions, suggesting that acute fluctuations in T may be more relevant for our understanding of the neuroendocrine mechanisms underlying variability in human aggression. ⋯ In addition, we discuss potential neural mechanisms underlying the effect of T dynamics on human aggression. Finally, we highlight several challenges for the field of social neuroendocrinology and discuss areas of research that may enhance our understanding of the complex bi-directional relationship between T and human social behavior.
-
Alzheimer's disease (AD) increases the risk for late-onset seizures and neuronal network abnormalities. An elevated co-occurrence of AD and seizures has been established in the more prevalent sporadic form of AD. Recent evidence suggests that nonconvulsive network abnormalities, including seizures and other electroencephalographic abnormalities, may be more commonly found in patients than previously thought. ⋯ Finally, the review discusses recent studies using antiepileptic drugs to rescue cognitive deficits in AD mouse models and human patients. Understanding the mechanistic link between epileptiform activity and AD is a research area of growing interest. Further understanding of the connection between neuronal hyperexcitability and Alzheimer's as well as the potential role of epileptiform activity in the progression of AD will be beneficial for improving treatment strategies.
-
Inflammation is an important event in ischemic injury. These immune responses begin with the expression of pro-inflammatory genes modulating transcription factors, such as nuclear factor-κB (NF-κB), activator protein-1 (AP-1), and signal transducers and activator of transcription-1 (STAT-1). The 70-kDa heat shock protein (Hsp70) can both induce and arrest inflammatory reactions and lead to improved neurological outcome in experimental brain injury and ischemia. ⋯ The results showed that heat stress led to Hsp70 overexpression which rendered neuroprotection after ischemia-like injury. Overexpression Hsp70 also interrupts the phosphorylation of IκB, JNK and p38 and blunts DNA binding of their transcription factors (NF-κB, AP-1 and STAT-1), effectively downregulating the expression of pro-inflammatory genes in heat-pretreated astrocytes. Taken together, these results suggest that overexpression of Hsp70 may protect against brain ischemia via an anti-inflammatory mechanism by interrupting the phosphorylation of upstream of transcription factors.