ABSTRACT
Activated microglia is considered to be involved in the progression of Alzheimer's disease (AD). We investigated the effect of amyloid-ß(1-40) (Aß(40) and exogenous agonists of Toll-like receptor (TLR) 1/2 (Pam(3)CSK(4)) and TLR4 (LPS) on neurons in primary murine neuron-microglia co-cultures. Neuronal viability, assessed by quantifying the number of intact neuronal extensions and their crossings using a newly developed Definiens Cognition Network Technology-based method, was significantly decreased after treatment with Pam(3)CSK(4), LPS, and Aß(40). Combined treatment with Aß(40) and Pam(3)CSK(4) or LPS had an additive effect. Hence, in patients with AD, synergistic microglial activation by Aß and bacterial products during infections might contribute to disease progression.
Subject(s)
Amyloid beta-Peptides/toxicity , Cognition/physiology , Image Processing, Computer-Assisted/methods , Microglia/pathology , Neurons/pathology , Peptide Fragments/toxicity , Toll-Like Receptors/agonists , Animals , Cell Survival/drug effects , Cell Survival/physiology , Coculture Techniques/methods , Cognition/drug effects , Lipopeptides/toxicity , Lipopolysaccharides/toxicity , Mice , Mice, Inbred C57BL , Microglia/drug effects , Microglia/microbiology , Nerve Net/drug effects , Nerve Net/microbiology , Nerve Net/pathology , Neurons/drug effects , Neurons/microbiology , Toll-Like Receptors/physiologyABSTRACT
Activity-dependent modifications of chromatin are believed to contribute to dramatic changes in neuronal circuitry. The mechanisms underlying these modifications are not fully understood. The histone variant H3.3 is incorporated in a replication-independent manner into different regions of the genome, including gene regulatory elements. It is presently unknown whether H3.3 deposition is involved in neuronal activity-dependent events. Here, we analyze the role of the histone chaperone DAXX in the regulation of H3.3 incorporation at activity-dependent gene loci. DAXX is found to be associated with regulatory regions of selected activity-regulated genes, where it promotes H3.3 loading upon membrane depolarization. DAXX loss not only affects H3.3 deposition but also impairs transcriptional induction of these genes. Calcineurin-mediated dephosphorylation of DAXX is a key molecular switch controlling its function upon neuronal activation. Overall, these findings implicate the H3.3 chaperone DAXX in the regulation of activity-dependent events, thus revealing a new mechanism underlying epigenetic modifications in neurons.
Subject(s)
Carrier Proteins/metabolism , Histone Chaperones/metabolism , Histones/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Membrane Potentials/physiology , Neurons/metabolism , Nuclear Proteins/metabolism , Animals , Calcineurin/metabolism , Calcium/metabolism , Cerebral Cortex/cytology , Cerebral Cortex/metabolism , Co-Repressor Proteins , Epigenesis, Genetic/physiology , Gene Expression Regulation/physiology , Genes, Immediate-Early , Mice , Mice, Knockout , Molecular Chaperones , Nerve Net/growth & development , Nerve Net/metabolism , Nerve Net/microbiology , Neural Conduction/physiology , Transcription, Genetic/physiologyABSTRACT
Post-mortem studies suggest that GABAergic neurotransmission is impaired in schizophrenia. However, it remains unclear if these changes occur early during development and how they impact overall network activity. To investigate this, we used a mouse model of prenatal infection with the viral mimic, polyriboinosinic-polyribocytidilic acid (poly I:C), a model based on epidemiological evidence that an immune challenge during pregnancy increases the prevalence of schizophrenia in the offspring. We found that prenatal infection reduced the density of parvalbumin- but not somatostatin-positive interneurons in the CA1 area of the hippocampus and strongly reduced the strength of inhibition early during postnatal development. Furthermore, using an intact hippocampal preparation in vitro, we found reduced theta oscillation generated in the CA1 area. Taken together, these results suggest that redistribution in excitatory and inhibitory transmission locally in the CA1 is associated with a significant alteration in network function. Furthermore, given the role of theta rhythm in memory, our results demonstrate how a risk factor for schizophrenia can affect network function early in development that could contribute to cognitive deficits observed later in the disease.
