Previous studies from our laboratory have shown that environmental enrichment (EE) in young rats results in improved learning ability and enhanced metabotropic glutamate receptor–dependent long-term ...potentiation (mGluR-dependent LTP) resulting from sustained activation of p70S6 kinase. Here, we investigated whether 1-month EE is sufficient to improve hippocampus-dependent learning and memory and enhance hippocampal LTP in 23–24 month-old Fischer 344 male rats. Aged rats were housed in environmentally enriched, socially enriched, or standard housing conditions. We find that aged rats exposed to 1-month of EE demonstrate enhanced learning and memory relative to standard housed controls when tested in the Morris water maze and novel object recognition behavioral tasks. Furthermore, we find that environmentally enriched rats perform significantly better than socially enriched or standard housed rats in the radial-arm water maze and display enhanced mGluR5-dependent hippocampal LTP. Enhanced hippocampal function results from activity-dependent increases in the levels of mGluR5, Homer1c, and phospho-p70S6 kinase. These findings demonstrate that a short exposure of EE to aged rats can have significant effects on hippocampal function.
Autosomal recessive loss-of-function mutations within the PARK2 gene functionally inactivate the E3 ubiquitin ligase parkin, resulting in neurodegeneration of catecholaminergic neurons and a familial ...form of Parkinson disease. Current evidence suggests both a mitochondrial function for parkin and a neuroprotective role, which may in fact be interrelated. The antiapoptotic effects of parkin have been widely reported, and may involve fundamental changes in the threshold for apoptotic cytochrome c release, but the substrate(s) involved in parkin dependent protection had not been identified. Here, we demonstrate the parkin-dependent ubiquitination of endogenous Bax comparing primary cultured neurons from WT and parkin KO mice and using multiple parkin-overexpressing cell culture systems. The direct ubiquitination of purified Bax was also observed in vitro following incubation with recombinant parkin. We found that parkin prevented basal and apoptotic stressinduced translocation of Bax to the mitochondria. Moreover, an engineered ubiquitination-resistant form of Bax retained its apo-ptotic function, but Bax KO cells complemented with lysine-mutant Bax did not manifest the antiapoptotic effects of parkin that were observed in cells expressing WT Bax. These data suggest that Bax is the primary substrate responsible for the antiapoptotic effects of parkin, and provide mechanistic insight into at least a subset of the mitochondrial effects of parkin.
We utilized forebrain organoids generated from induced pluripotent stem cells of patients with a syndromic form of Autism Spectrum Disorder (ASD) with a homozygous protein-truncating mutation in ...CNTNAP2, to study its effects on embryonic cortical development. Patients with this mutation present with clinical characteristics of brain overgrowth. Patient-derived forebrain organoids displayed an increase in volume and total cell number that is driven by increased neural progenitor proliferation. Single-cell RNA sequencing revealed PFC-excitatory neurons to be the key cell types expressing CNTNAP2. Gene ontology analysis of differentially expressed genes (DEgenes) corroborates aberrant cellular proliferation. Moreover, the DEgenes are enriched for ASD-associated genes. The cell-type-specific signature genes of the CNTNAP2-expressing neurons are associated with clinical phenotypes previously described in patients. The organoid overgrowth phenotypes were largely rescued after correction of the mutation using CRISPR-Cas9. This CNTNAP2-organoid model provides opportunity for further mechanistic inquiry and development of new therapeutic strategies for ASD.
Parkinson's disease (PD)-associated E3 ubiquitin ligase Parkin is enriched at glutamatergic synapses, where it ubiquitinates multiple substrates, suggesting that its mutation/loss-of-function could ...contribute to the etiology of PD by disrupting excitatory neurotransmission. Here, we evaluate the impact of four common PD-associated Parkin point mutations (T240M, R275W, R334C, G430D) on glutamatergic synaptic function in hippocampal neurons.
We find that expression of these point mutants in cultured hippocampal neurons from Parkin-deficient and Parkin-null backgrounds alters NMDA and AMPA receptor-mediated currents and cell-surface levels and prevents the induction of long-term depression. Mechanistically, we demonstrate that Parkin regulates NMDA receptor trafficking through its ubiquitination of GluN1, and that all four mutants are impaired in this ubiquitinating activity. Furthermore, Parkin regulates synaptic AMPA receptor trafficking via its binding and retention of the postsynaptic scaffold Homer1, and all mutants are similarly impaired in this capacity.
Our findings demonstrate that pathogenic Parkin mutations disrupt glutamatergic synaptic transmission in hippocampal neurons by impeding NMDA and AMPA receptor trafficking. Such effects may contribute to the pathophysiology of PD in PARK2 patients.
Autosomal-recessive mutations in the Parkin gene are the second most common cause of familial Parkinson's disease (PD). Parkin deficiency leads to the premature demise of the catecholaminergic ...neurons of the ventral midbrain in familial PD. Thus, a better understanding of parkin function may elucidate molecular aspects of their selective vulnerability in idiopathic PD. Numerous lines of evidence suggest a mitochondrial function for parkin and a protective effect of ectopic parkin expression. Since mitochondria play a critical role in cell survival/cell death through regulated cytochrome c release and control of apoptosis, we sought direct evidence of parkin function in this pathway. Mitochondria were isolated from cells expressing either excess levels of human parkin or shRNA directed against endogenous parkin and then treated with peptides corresponding to the active Bcl-2 homology 3 (BH3) domains of pro-apoptotic proteins and the threshold for cytochrome c release was analyzed. Data obtained from both rodent and human neuroblastoma cell lines showed that the expression levels of parkin were inversely correlated with cytochrome c release. Parkin was found associated with isolated mitochondria, but its binding per se was not sufficient to inhibit cytochrome c release. In addition, pathogenic parkin mutants failed to influence cytochrome c release. Furthermore, PINK1 expression had no effect on cytochrome c release, suggesting a divergent function for this autosomal recessive PD-linked gene. In summary, these data demonstrate a specific autonomous effect of parkin on mitochondrial mechanisms governing cytochrome c release and apoptosis, which may be relevant to the selective vulnerability of certain neuronal populations in PD.
The ALICE Zero Degree Calorimeters (ZDC) provide information about event geometry in heavy-ion collisions through the detection of spectator nucleons and allow to estimate the delivered luminosity. ...They are also very useful in p–A collisions, allowing an unbiased estimation of collision centrality. The Run 3 operating conditions will involve a tenfold increase in instantaneous luminosity in heavy-ion collisions, with event rates that, taking into account the different processes, could reach 5 MHz in the ZDCs. The challenges posed by this demanding environment lead to a redesign of the readout system and to the transition to a continuous acquisition. The new system is based on 12 bit, 1 Gsps FMC digitizers that will continuously sample the 26 ZDC channels. Triggering, pedestal estimation and luminosity measurements will be performed on FPGA directly connected to the front-end. The new readout system and the performances foreseen in Run 3 are presented.
•Neuroinflammation underlies cognitive decline in postoperative cognitive delirium and Alzheimer’s disease.•The susceptibility to neuroinflammatory challenges increases with age.•Neuroinflammation is ...exaggerated in the aging brain.•POD and AD pathogenesis have common immune links.•POD serves as a model to study late-stage cognitive decline and AD.
Alzheimer’s disease (AD) is a progressive neurodegenerative disease that targets memory and cognition, and is the most common form of dementia among the elderly. Although AD itself has been extensively studied, very little is known about early-stage preclinical events and/or mechanisms that may underlie AD pathogenesis. Since the majority of AD cases are sporadic in nature, advancing age remains the greatest known risk factor for AD. However, additional environmental and epigenetic factors are thought to accompany increasing age to play a significant role in the pathogenesis of AD. Postoperative cognitive delirium (POD) is a behavioral syndrome that primarily occurs in elderly patients following a surgical procedure or injury and is characterized by disruptions in cognition. Individuals that experience POD are at an increased risk for developing dementia and AD compared to normal aging individuals. One way in which cognitive function is affected in cases of POD is through activation of the inflammatory cascade following surgery or injury. There is compelling evidence that immune challenges (surgery and/or injury) associated with POD trigger the release of pro-inflammatory cytokines into both the periphery and central nervous system. Thus, it is possible that cognitive impairments following an inflammatory episode may lead to more severe forms of dementia and AD pathogenesis. Here we will discuss the inflammation associated with POD, and highlight the advantages of using POD as a model to study inflammation-evoked cognitive impairment. We will explore the possibility that advancing age and immune challenges may provide mechanistic evidence correlating early life POD with AD. We will review and propose neural mechanisms by which cognitive impairments occur in cases of POD, and discuss how POD may augment the onset of AD.
The NA60 experiment has studied low-mass muon pair production in proton–nucleus collisions with a system of Be, Cu, In, W, Pb and U targets, using a 400 GeV proton beam at the CERN SPS. The ...transverse momentum spectra of the
ρ
/
ω
and
ϕ
mesons are measured in the full
p
T
range accessible, from
p
T
=
0
up to
2
GeV/c
. The nuclear dependence of the production cross sections of the
η
,
ω
and
ϕ
mesons has been found to be consistent with the power law
σ
pA
∝
A
α
, with the
α
parameter increasing as a function of
p
T
for all the particles, and an approximate hierarchy
α
η
≈
α
ϕ
>
α
ω
. The cross section ratios
σ
η
/
σ
ω
,
σ
ρ
/
σ
ω
and
σ
ϕ
/
σ
ω
have been studied as a function of the size A of the production target, and an increase of the
η
and
ϕ
yields relative to the
ω
is observed from p–Be to p–U collisions.
We report on a precision measurement of low-mass muon pairs in 158 AGeV indium-indium collisions at the CERN SPS. A significant excess of pairs is observed above the yield expected from neutral meson ...decays. The unprecedented sample size of 360,000 dimuons and the good mass resolution of about 2% allow us to isolate the excess by subtraction of the decay sources. The shape of the resulting mass spectrum is consistent with a dominant contribution from pi+pi- -->rho -->mu+mu- annihilation. The associated space-time averaged spectral function shows a strong broadening, but essentially no shift in mass. This may rule out theoretical models linking hadron masses directly to the chiral condensate.
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