Neonatal therapy with clenbuterol and salmeterol restores spinogenesis and dendritic complexity in the dentate gyrus of the Ts65Dn model of Down syndrome

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Increases of SET level and translocation are correlated with tau hyperphosphorylation at ser202/thr205 in CA1 of Ts65Dn mice

International audienceSET is a multifunctional protein, but when present in the cytoplasm, acts as a powerful inhibitor of phosphatase 2A. We previously observed that in CA1 of Down syndrome (DS) patients, the level of SET is increased, and SET is translocated to the cytoplasm and associated with the hyperphosphorylation of tau at ser202/thr205. The presence of SET in the cytoplasm in DS brains may play a role in the progression of the disease. Here, we show that in CA1 of 3-month-old Ts65Dn mice modeling DS, SET level is increased, and SET is translocated to the cytoplasm and associated with tau hyperphosphorylations at ser202/ thr205 and with amyloid precursor protein caspase cleaved as observed in Alzheimer disease brains. Tau hyperphosphorylation at ser356 and activation of other phosphatase 2A targets such as the mammalian target of rapamycin and adenosine monophosphate protein kinases were also observed, suggesting deleterious mechanisms. We propose Ts65Dn mice as a model for therapeutic approaches focused on SET overexpression and its cytoplasmic translocation to slow down disease progression

Neonatal therapy with clenbuterol and salmeterol restores spinogenesis and dendritic complexity in the dentate gyrus of the Ts65Dn model of Down syndrome

Down syndrome (DS), a neurodevelopmental disorder caused by triplication of chromosome 21, is characterizedby intellectual disability. In DS, defective neurogenesis causes an overall reduction in the number of neuronspopulating the brain and defective neuron maturation causes dendritic hypotrophy and reduction in the densityof dendritic spines. No effective therapy currently exists for the improvement of brain development in in-dividuals with DS. Drug repurposing is a strategy for identifying new medical use for approved drugs. A drugscreening campaign showed that the \u3b22-adrenergic receptor (\u3b22-AR) agonists clenbuterol hydrochloride (CLEN)and salmeterol xinafoate (SALM) increase the proliferation rate of neural progenitor cells from the Ts65Dnmodel of DS. The goal of the current study was to establish their efficacyinvivo, in the Ts65Dn model. We foundthat, at variance with theinvitroexperiments, treatment with CLEN or SALM did not restore neurogenesis in thehippocampus of Ts65Dn mice treated during the postnatal (P) period P3-P15. In Ts65Dn mice treated with CLENor SALM, however, dendritic spine density and dendritic arborization of the hippocampal granule cells wererestored and the lowest dose tested here (0.01 mg/kg/day) was sufficient to elicit these effects. CLEN and SALMare used in children as therapy for asthma and, importantly, they pass the blood-brain barrier. Our study sug-gests that treatment with these \u3b22-AR agonists may be a therapy of choice in order to correct dendritic devel-opment in DS but is not suitable to rescue neurogenesis

Revisiting the neural role of estrogen receptor beta in male sexual behavior by conditional mutagenesis

International audienceEstradiol derived from neural aromatization of gonadal testosterone plays a key role in the perinatal organization of the neural circuitry underlying male sexual behavior. The aim of this study was to investigate the contribution of neural estrogen receptor (ER) β in estradiol-induced effects without interfering with its peripheral functions. For this purpose, male mice lacking ERβ in the nervous system were generated. Analyses of males in two consecutive tests with a time interval of two weeks showed an effect of experience, but not of genotype, on the latencies to the first mount, intromission, pelvic thrusting and ejaculation. Similarly, there was an effect of experience, but not of genotype, on the number of thrusts and mating length. Neural ERβ deletion had no effect on the ability of males to adopt a lordosis posture in response to male mounts, after castration and priming with estradiol and progesterone. Indeed, only low percentages of both genotypes exhibited a low lordosis quotient. It also did not affect their olfactory preference. Quantification of tyrosine hydroxylase- and kisspeptin-immunoreactive neurons in the preoptic area showed unaffected sexual dimorphism of both populations in mutants. By contrast, the number of androgen receptor- and ERα-immunoreactive cells was significantly increased in the bed nucleus of stria terminalis of mutant males

Long‐lasting correction of in vivo LTP and cognitive deficits of mice modelling Down syndrome with an α5‐selective GABAA inverse agonist

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Neural Androgen Receptor Deletion Impairs the Temporal Processing of Objects and Hippocampal CA1-Dependent Mechanisms

International audienceWe studied the role of testosterone, mediated by the androgen receptor (AR), in modulating temporal order memory for visual objects. For this purpose, we used male mice lacking AR specifically in the nervous system. Control and mutant males were gonadectomized at adulthood and supplemented with equivalent amounts of testosterone in order to normalize their hormonal levels. We found that neural AR deletion selectively impaired the processing of temporal information for visual objects, without affecting classical object recognition or anxiety-like behavior and circulating corticosterone levels, which remained similar to those in control males. Thus, mutant males were unable to discriminate between the most recently seen object and previously seen objects, whereas their control littermates showed more interest in exploring previously seen objects. Because the hippocampal CA1 area has been associated with temporal memory for visual objects, we investigated whether neural AR deletion altered the functionality of this region. Electrophysiological analysis showed that neural AR deletion affected basal glutamate synaptic transmission and decreased the magnitude of N-methyl-D-aspartate receptor (NMDAR) activation and high-frequency stimulation induced long-term potentiation. The impairment of NMDAR function was not due to changes in protein levels of receptor. These results provide the first evidence for the modulation of temporal processing of information for visual objects by androgens, via AR activation , possibly through regulation of NMDAR signaling in the CA1 area in male mice

Synaptic plasticity in the hippocampal CA1 area of AR^fl/Y and AR^NesCre male mice.

<p>(<b>a-b</b>) Comparison of the time course of mean long-term potentiation (LTP) induced by high-frequency stimulation (HFS) (<b>a</b>; 9 slices from 7 animals per genotype) or by theta-burst stimulation (TBS) (<b>b</b>; 12 slices from 7–8 males per genotype). *<i>p</i> < 0.05 <i>versus</i> control. (<b>c</b>) Comparison of the time course of mean long-term depression (LTD) induced by low-frequency stimulation (LFS) in males (10–11 slices from 5–6 animals per genotype).</p

Basal synaptic transmission in the hippocampal CA1 area of AR^fl/Y and AR^NesCre male mice.

<p>(<b>a-b</b>) Input/output (I/O) curves of presynaptic fiber volleys (PFVs) (<b>a</b>) and field excitatory postsynaptic potentials (fEPSPs) (<b>b</b>) induced in control medium by the electrical stimulation of glutamatergic afferents (44 slices from 8 males per genotype). PFV magnitude was significantly smaller in AR^NesCre males only at the highest stimulus intensity (*<i>p</i> < 0.05), whereas fEPSP values were already lower at lower intensities (**<i>p</i> < 0.01). (<b>c</b>) Upper panel, representative paired-pulse facilitation (PPF) of fEPSPs induced in a AR^NesCre male by two successive stimuli (arrows) delivered with a 30 ms inter-stimulus interval. Lower panel, mean PPF magnitude (28–29 slices per genotype).</p

Temporal order memory and object recognition in AR^fl/Y and AR^NesCre male mice.

<p>(<b>a-b</b>) Familiarization and testing phases of the temporal order (<b>a</b>) and novelty detection (<b>b</b>) tasks. (<b>c-d</b>) Discrimination Indexes in the temporal order (<b>c</b>) and novelty detection tasks (<b>d</b>) for males (n = 8–9 males per genotype). ***<i>p</i> < 0.001 <i>versus</i> object A; ^#<i>p</i> < 0.05 <i>versus</i> controls.</p

Anxiety state level and corticosterone levels in AR^fl/Y and AR^NesCre male mice.

<p><b>(a-b)</b> Time spent and latency to enter in the open arms of the EPM (<b>a</b>) or the O-maze (<b>b</b>) for controls and mutants (n = 8–11 males per genotype). (<b>f</b>) Corticosterone secretion during the circadian cycle (n = 8–11 males per genotype).</p