Biology subjects

Marneffe, C.

Publications and source records attributed to Marneffe, C..

4 recordsLinked to original sources

bioRxiv2024

Early changes in the properties of CA3 engram cells explored with a novel viral tool

Forming new memories after a one-time experience requires initial encoding then consolidation over time. During learning, multimodal information converges onto the hippocampus, activating sparse neuronal assemblies which are thought to form a memory representation through concerted activity and synaptic interconnectivity. In this work, we use a novel tool for fast fluorescent labeling of engram neurons (FLEN). FLEN is based on c-Fos activity-dependent transient expression of a destabilized fluorescent marker ZsGreen1 rapidly after one-trial learning. With FLEN, we explore the electrophysiological properties of c-Fos activated CA3 pyramidal neurons a few hours following one-trial learning of an episodic-like memory. In parallel, we employ the Robust Activity Marker (RAM) system, which provides activity-dependent labelling 24 hours following a novel experience. Comparing FLEN+ and RAM+ neurons allows to characterize how the properties of neuronal assemblies evolve during an initial phase of consolidation. Whereas no difference was observed in the excitability of FLEN+ vs. FLEN-neurons, RAM+ neurons were more excitable than RAM-neurons. This suggests that CA3 pyramidal neurons recruited in an engram progressively acquire increased excitability as compared to neurons which were not activated by the one-trial contextual memory task. On the other hand, like RAM+ neurons, FLEN+ CA3 neurons show an increased number of excitatory inputs. Overall, with the FLEN strategy, we can show that both the intrinsic excitability and the synaptic properties of CA3 pyramidal neurons undergo progressive plastic changes over the first day following a one-trial memory task.

neuroscience↗

bioRxiv2024

Abrogation of presynaptic facilitation at hippocampal mossy fiber synapses impacts neural ensemble activity and spatial memory

Presynaptic short-term plasticity is thought to play a major role in the process of spike transfer within local circuits. Mossy fiber synapses between the axons of dentate gyrus (DG) granule cells and CA3 pyramidal cells (Mf-CA3 synapses) display a remarkable extent of presynaptic plasticity which endows these synaptic connections with detonator properties. The pattern of action potential firing, in the form of high frequency bursts in the DG, strongly controls the amplitude of synaptic responses and information transfer to CA3. Here we have investigated the role of presynaptic facilitation at Mf-CA3 synapses in the operation of CA3 circuits in vivo and in memory encoding. Syt7, a calcium sensor necessary for presynaptic facilitation, was selectively abrogated, in DG granule cells using Syt7 conditional KO mice (DG Syt7 KO mice). In hippocampal slices, we extend previous analysis to show that short-term presynaptic facilitation is selectively suppressed at Mf-CA3 synapses in the absence of Syt7, without any impact on basal synaptic properties and long-term potentiation. Short-term plasticity was found to be crucial for spike transfer between the DG and CA3 in conditions of naturalistic patterns of presynaptic firing. At the network level, in awake head-fixed mice, the abrogation of short-term plasticity largely reduced the co-activity of CA3 pyramidal cells. Finally, whereas DG Syt7 KO mice are not impaired in behavioral tasks based on pattern separation, they show deficits in spatial memory tasks which rely on the process of pattern completion. These results shed new light on the role of the detonator properties of DG-CA3 synapses, and give important insights into how this key synaptic feature translate at the population and behavioral levels.

neuroscience↗

bioRxiv2023

Unravelling cell type specific response to Parkinson's Disease at single cell resolution

Parkinsons Disease (PD) is the second most common neurodegenerative disorder and is generally characterized by impaired motor functions. It currently affects 6.3 million people aged 60 years and more, worldwide. The pathological hallmarks of PD are Lewy bodies (abnormal aggregation of -synuclein inside cells), which are observed primarily in the substantia nigra (SN) region of the midbrain. It is yet not known how different cell types in SN respond during PD and what are the molecular mechanisms underlying neurodegeneration. To address this question, we generated a large-scale single cell transcriptomics dataset from human post-mortem SN tissue of 29 donors including 15 sporadic cases and 14 controls. We obtained data for a total of [~]80K nuclei, representing major cell types of the brain (including neurons, astrocytes, microglia and oligodendrocytes). Pathway and differential gene expression analysis revealed multicellular character of PD pathology involving major cellular response from neuronal and glial cells.

bioinformatics↗

bioRxiv2019

AAV mediated delivery of a novel anti-BACE1 VHH reduces Abeta in an Alzheimer’s disease mouse model

Single domain antibodies (VHH) are potentially disruptive therapeutics, with important biological value for treatment of several diseases, including neurological disorders. However, VHH have not been widely used in the central nervous system (CNS), as it is hard to reach therapeutic levels, both because of their restricted blood-brain-barrier penetration and their apparent rapid clearance from the parenchyma. Here, we propose a gene transfer strategy based on adeno-associated virus (AAV)-based vectors to deliver VHH directly into the CNS, ensuring continuous production at therapeutic levels. As a proof-of-concept, we explored the potential of AAV-delivered VHH to inhibit BACE1, a well-characterized target in Alzheimers disease. First, we generated a panel of VHHs targeting BACE1. One of them, VHH-B9, showed high selectivity for BACE1 and efficacy in lowering BACE1 activity in vitro. We then went on to demonstrate significant reductions in amyloid beta (A{beta}) levels after AAV-based delivery of VHH-B9 into the CNS of a mouse model of cerebral amyloidosis. These results constitute a novel therapeutic approach for neurodegenerative diseases, which is applicable to a range of CNS disease targets.

neuroscience↗