Biology subjects

Merino-Serrais, P.

Publications and source records attributed to Merino-Serrais, P..

4 recordsLinked to original sources

bioRxiv2021

A brain atlas of synapse protein lifetime across the mouse lifespan.

Protein turnover is required for synapse maintenance and remodelling and may impact memory duration. We quantified the lifetime of postsynaptic protein PSD95 in individual excitatory synapses across the mouse brain and lifespan, generating the Protein Lifetime Synaptome Atlas. Excitatory synapses have a wide range of protein lifetimes that may extend from a few hours to several months, with distinct spatial distributions in dendrites, neuron types and brain regions. Short protein lifetime (SPL) synapses are enriched in developing animals and in regions controlling innate behaviors, whereas long protein lifetime (LPL) synapses accumulate during development, are enriched in the cortex and CA1 where memories are stored, and are preferentially preserved in old age. The protein lifetime synaptome architecture is disrupted in an autism model, with synapse protein lifetime increased throughout the brain. These findings add a further layer to synapse diversity in the brain and enrich prevailing concepts in behavior, development, ageing and brain repair.

neuroscience↗

bioRxiv2021

Sex-dependent effects of CYP46A1 overexpression on cognitive function during aging

Cholesterol turnover and CYP46A1 regulation are reported to be crucial for memory functions. An increasing body of evidence shows that CYP46A1 activation is able to reduce Alzheimers Disease (AD) pathological processes. In this study we report for the first time that CYP46A1 overexpression and increase of 24S-hydroxycholesterol (24OH) induces sex-specific changes in synaptic functions in aged mice, being beneficial in females while detrimental in males. The positive effects on cognition in aged CYP46A1 overexpressing female mice were accompanied by morphological changes in dendritic spines and enhancement of estrogen receptor signaling in hippocampus. In aged males, CYP46A1 overexpression leads to anxiety-like behavior and worsening of spatial memory, followed by decreased dendritic spine density and higher 5-dihydrotestosterone (DHT) levels in hippocampus. Further, analysis of cerebrospinal fluid (CSF) from AD, mild cognitive impairment and healthy patients revealed that 24OH was negatively associated to markers of neurodegeneration in women but not in men. Based on our results, CYP46A1 activation may represent a pharmacological target that could specifically enhance brain estrogen receptor signaling in women at risk of developing AD. Finally, this study highlights the importance of taking into account the sex-dimension in both preclinical and clinical studies of neurodegenerative diseases like AD.

animal behavior and cognition↗

bioRxiv2020

Dendritic spines are lost in clusters in patients with Alzheimers disease

Alzheimers disease (AD) is a progressive neurodegenerative disorder characterized by a deterioration of neuronal connectivity. The pathological accumulation of tau in neurons is one of the hallmarks of AD and has been connected to the loss of dendritic spines of pyramidal cells, which are the major targets of cortical excitatory synapses and key elements in memory storage. However, the detailed mechanisms underlying the loss of dendritic spines in individuals with AD are still unclear. Here, we used graph-theory approaches to compare the distribution of dendritic spines from neurons with and without tau pathology of AD individuals. We found that the presence of tau pathology determines the loss of dendritic spines in clusters, ruling out alternative models where spine loss occurs at random locations. Since memory storage has been associated with synaptic clusters, the present results provide a new insight into the mechanisms by which tau drives synaptic damage in AD, paving the way to memory deficits through alterations of spine organization.

neuroscience↗

bioRxiv2019

Lithium treatment reverses irradiation-induced changes in rodent neural progenitors

Cranial radiotherapy in children has detrimental effects on cognition, mood, and social competence in young cancer survivors. Treatments harnessing hippocampal neurogenesis are currently of great relevance in this context, and we previously showed that voluntary running introduced long after irradiation rescued hippocampal neurogenesis in young mice (Naylor et al. 2008a). Lithium, a well-known mood stabilizer, has both neuroprotective, pro-neurogenic as well as anti-tumor effects, and in the current study we introduced lithium treatment 4 weeks after irradiation, analogous to the voluntary running study. Female mice received a single 4 Gy whole-brain irradiation dose at postnatal day (PND) 21 and were randomized to 0.24% Li2CO3 chow or normal chow from PND 49 to 77. Hippocampal neurogenesis was assessed at PND 77, 91 and 105. We found that lithium treatment had a pro-proliferative effect on neural progenitors and promoted neuronal integration upon its discontinuation. Gene expression profiling and DNA methylation analysis identified two novel factors related to the observed effects, Tppp, associated with proliferation, and GAD2/65, associated with neuronal signaling. Our results show that lithium treatment reverses irradiation-induced impairment of hippocampal neurogenesis even when introduced long after the injury. We propose that lithium treatment should be intermittent in order to first make neural progenitors proliferate and then, upon discontinuation, allow them to differentiate. Our findings suggest that pharmacological treatment of cognitive so-called late effects in childhood cancer survivors is possible.

neuroscience↗