Blank T

References (2)

Title : Dicer Deficiency Differentially Impacts Microglia of the Developing and Adult Brain - Varol_2017_Immunity_46_1030
Author(s) : Varol D , Mildner A , Blank T , Shemer A , Barashi N , Yona S , David E , Boura-Halfon S , Segal-Hayoun Y , Chappell-Maor L , Keren-Shaul H , Leshkowitz D , Hornstein E , Fuhrmann M , Amit I , Maggio N , Prinz M , Jung S
Ref : Immunity , 46 :1030 , 2017
Abstract : Microglia seed the embryonic neuro-epithelium, expand and actively sculpt neuronal circuits in the developing central nervous system, but eventually adopt relative quiescence and ramified morphology in the adult. Here, we probed the impact of post-transcriptional control by microRNAs (miRNAs) on microglial performance during development and adulthood by generating mice lacking microglial Dicer expression at these distinct stages. Conditional Dicer ablation in adult microglia revealed that miRNAs were required to limit microglial responses to challenge. After peripheral endotoxin exposure, Dicer-deficient microglia expressed more pro-inflammatory cytokines than wild-type microglia and thereby compromised hippocampal neuronal functions. In contrast, prenatal Dicer ablation resulted in spontaneous microglia activation and revealed a role for Dicer in DNA repair and preservation of genome integrity. Accordingly, Dicer deficiency rendered otherwise radio-resistant microglia sensitive to gamma irradiation. Collectively, the differential impact of the Dicer ablation on microglia of the developing and adult brain highlights the changes these cells undergo with time.
ESTHER : Varol_2017_Immunity_46_1030
PubMedSearch : Varol_2017_Immunity_46_1030
PubMedID: 28636953

Title : Stress-induced alternative splicing of acetylcholinesterase results in enhanced fear memory and long-term potentiation - Nijholt_2004_Mol.Psychiatry_9_174
Author(s) : Nijholt I , Farchi N , Kye M , Sklan EH , Shoham S , Verbeure B , Owen D , Hochner B , Spiess J , Soreq H , Blank T
Ref : Mol Psychiatry , 9 :174 , 2004
Abstract : Stress insults intensify fear memory; however, the mechanism(s) facilitating this physiological response is still unclear. Here, we report the molecular, neurophysiological and behavioral findings attributing much of this effect to alternative splicing of the acetylcholinesterase (AChE) gene in hippocampal neurons. As a case study, we explored immobilization-stressed mice with intensified fear memory and enhanced long-term potentiation (LTP), in which alternative splicing was found to induce overproduction of neuronal 'readthrough' AChE-R (AChE-R). Selective downregulation of AChE-R mRNA and protein by antisense oligonucleotides abolished the stress-associated increase in AChE-R, the elevation of contextual fear and LTP in the hippocampal CA1 region. Reciprocally, we intrahippocampally injected a synthetic peptide representing the C-terminal sequence unique to AChE-R. The injected peptide, which has been earlier found to exhibit no enzymatic activity, was incorporated into cortical, hippocampal and basal nuclei neurons by endocytosis and retrograde transport and enhanced contextual fear. Compatible with this hypothesis, inherited AChE-R overexpression in transgenic mice resulted in perikaryal clusters enriched with PKCbetaII, accompanied by PKC-augmented LTP enhancement. Our findings demonstrate a primary role for stress-induced alternative splicing of the AChE gene to elevated contextual fear and synaptic plasticity, and attribute to the AChE-R splice variant a major role in this process.
ESTHER : Nijholt_2004_Mol.Psychiatry_9_174
PubMedSearch : Nijholt_2004_Mol.Psychiatry_9_174
PubMedID: 14581933