Freddy Jeanneteau

Institut de Génomique Fonctionnelle CNRS INSERM Univ Montpellier · Neuroscience

The exact neuropathological mechanism by which dementia process unfolds is under intense scrutiny. The disease affects about 38 million people worldwide, 70% of which are clinically diagnosed with Alzheimer's disease (AD). If the destruction of synapses essential for learning, planning and decision‐making is part of the problem, must the restoratio...

Soluble and solid amyloid pathways reveal differential dynamics of glutamatergic synapses that depend on neurocentric cortisol receptor signaling

Dissociation between the healthy and toxic effects of cortisol, a major stress‐responding hormone has been a widely used strategy to develop anti‐inflammatory glucocorticoids with fewer side effects. Such strategy falls short when treating brain disorders as timing and activity state within large‐scale neuronal networks determine the physiological...

Background Research in recent years firmly established that microglial cells play an important role in the pathogenesis of Alzheimer's disease (AD). In parallel, a series of studies showed that, under both homeostatic and pathological conditions, microglia are a heterogeneous cell population. In AD, amyloid-β (Aβ) plaque-associated microglia (PAM)...

Affective touch is necessary for the neuro-development and social interactions. Do tactile neurons innervating the skin detect affective touch and regulates behaviors? We targeted C-low threshold mechanoreceptors (C-LTMR) using DREADDs strategy. Reducing C-LTMR activity decreased sociability. Promoting C-LTMR function affected pleasant behaviors an...

Affective touch is necessary for proper neurodevelopment and sociability. However, it remains unclear how the neurons innervating the skin detect affective and social behaviors. The C low-threshold mechanoreceptors (C-LTMRs), a specific population of somatosensory neurons in mice, appear particularly well suited, physiologically and anatomically, t...

Aberrant cortisol and activation of the glucocorticoid receptor (GR) play an essential role in age-related progression of Alzheimer's disease (AD). However, the GR pathways required for influencing the pathobiology of AD dementia remain unknown. To address this, we studied an early phase of AD-like progression in the well-established APP/PS1 mouse...

The complexity of the classical inverted U-shaped relationship between cortisol levels and responses transposable to stress reactivity has led to an incomplete understanding of the mechanisms enabling healthy and toxic effects of stress on brain and behavior. A clearer, more detailed, picture of those relationships can be obtained by integrating co...

Attention to key features of contexts and things is a necessary tool for all organisms. Detecting these salient features of cues, or simply, salience, can also be affected by exposure to traumatic stress, as has been widely reported in individuals suffering from Post-Traumatic Stress Disorder (PTSD). Interestingly, similar observations have been ro...

longitudinal in vivo imaging of fluorescent probes targeting mitochondria in pyramidal neurons of mouse cortex. We imaged ATP, H2O2, mitochondria and dendritic spines before and after chronic unpredictable stress and after an acute challenge to monitor how the cost of plasticity distributes in dendritic territories.

Metabolic adaptation is a critical feature of synaptic plasticity. Indeed, synaptic plasticity requires the utilization and resupply of metabolites, in particular when the turnover is high and fast such as in stress conditions. What accounts for the localized energy burden of the post-synaptic compartment to the build up of chronic stress is curren...

Affective touch is necessary for proper neurodevelopment and sociability. However, it is still unclear how the neurons innervating the skin detect affective and social behaviours. To clarify this matter, we targeted a specific population of somatosensory neurons in mice, named C-low threshold mechanoreceptors (C-LTMRs), that appears particularly we...

Intellectual and social disabilities are common comorbidities in adolescents and adults with MAGEL2 gene deficiency characterizing the Prader-Willi and Schaaf-Yang neurodevelopmental syndromes. The cellular and molecular mechanisms underlying the risk for autism in these syndromes are not understood. We ask whether vasopressin functions are altered...

The diversity of actions of the glucocorticoid stress hormones among individuals and within organs, tissues and cells is shaped by age, gender, genetics, metabolism, and the quantity of exposure. However, such factors cannot explain the heterogeneity of responses in the brain within cells of the same lineage, or similar tissue environment, or in th...

Twitter: @Dhuzard / Researchgate: link • We suggest that some neurotrophic factors secreted under specific conditions (at molecular, cellular, network and behavioral levels) may differently alter GR-mediated stress responses. • At the different levels: higher diversity promotes flexibility while scarcity may induce maladaptability. • The susceptibi...

Microtubule (MT) plus-end tracking proteins (+TIPs) are central players in the coordination between the MT and actin cytoskeletons in growth cones (GCs) during axon guidance. The +TIP Navigator-1 (NAV1) is expressed in the developing nervous system, yet its neuronal functions remain poorly elucidated. Here, we report that NAV1 controls the dynamics...

Functional imaging in behaving animals is essential to explore brain functions. Real-time optical imaging of brain functions is limited by light scattering, skull distortion, timing resolution and subcellular precision that altogether, make challenging the rapid acquisition of uncorrupted functional data of cells integrated de novo in the neuroglio...

Background: Pesticide residues have contaminated our environment and nutrition over the last century. Although these compounds are present at very low concentrations their long-term effects on human health is of concern. The link between pesticide residues and Alzheimer’s disease is not clear and difficult to establish. To date, no in vivo experime...

Supplemental figures and tables - Fungicide Residues Exposure and b-amyloid Aggregation in a Mouse Model of Alzheimer’s Disease.

Collective actions of vasopressin and oxytocin determine social salience. Borie et al. find that the degree of social novelty moderates a dialogue between networks secreting social salience hormones in the lateral septum, a region organizing sequential content of sensory experiences. Social withdrawal of mice lacking the autism gene Magel2 is allev...

Intellectual and social disabilities are common comorbidities in adolescents and adults with Magel2 gene deficiency characterizing the Prader-Willi and Schaaf-Yang neurodevelopmental syndromes. The cellular and molecular mechanisms underlying the risk for autism in these syndromes are unexplored. Here we used Magel2 knockout mice combined with opto...

Significance Signal transduction upon activation of receptor tyrosine kinases by neurotrophins and nuclear receptors by glucocorticoids is essential for homeostasis. Phosphorylation (PO 4 ) is one way these receptors communicate with one another to support homeostatic reactions in learning and memory. Using a newly developed glucocorticoid receptor...

Stress can either promote or impair learning and memory. Such opposing effects depend on whether synapses persist or decay after learning. Maintenance of new synapses formed at the time of learning upon neuronal network activation depends on the stress hormone activated glucocorticoid receptor (GR) and neurotrophic factor release. Whether and how c...

Behavioral choices made by the brain during stress depend on glucocorticoid and brain-derived neurotrophic factor (BDNF) signaling pathways acting in synchrony in the mesolimbic (reward) and corticolimbic (emotion) neural networks. Deregulated expression of BDNF and glucocorticoid receptors in brain valuation areas may compromise the integration of...

Reorganization of the neurovascular unit has been suggested in the epileptic brain, although the dynamics and functional significance remain unclear. Here, we tracked the in vivo dynamics of perivascular mural cells as a function of electroencephalogram (EEG) activity following status epilepticus. We segmented the cortical vascular bed to provide a...

The energetic costs of behavioral chronic stress are unlikely to be sustainable without neuronal plasticity. Mitochondria have the capacity to handle synaptic activity up to a limit before energetic depletion occurs. Protective mechanisms driven by the induction of neuronal genes likely evolved to buffer the consequences of chronic stress on excita...

The energetic costs of behavioral chronic stress are unlikely to be sustainable without neuronal plasticity. Mitochondria have the capacity to handle synaptic activity up to a limit before energetic depletion occurs. Protective mechanisms driven by the induction of neuronal genes likely evolved to buffer the consequences of chronic stress on excita...

Hippocampal CA1 pyramidal neurons, a major component of the medial temporal lobe memory circuit, are selectively vulnerable during the progression of Alzheimer's disease (AD). The cellular mechanism(s) underlying degeneration of these neurons and the relationship to cognitive performance remains largely undefined. Here, we profiled neurotrophin and...

Glucocorticoids via the glucocorticoid receptor (GR) have effects on a variety of cell types, eliciting important physiological responses via changes in gene expression and signaling. Although decades of research have illuminated the mechanism of how this important steroid receptor controls gene expression using in vitro and cell culture–based appr...

Remodeling of the brain vasculature is a common trait of brain pathologies. In vivo imaging techniques are fundamental to detect cerebrovascular plasticity or damage occurring overtime and in relation to neuronal activity or blood flow. In vivo two-photon microscopy allows the study of the structural and functional plasticity of large cellular unit...

Glucocorticoid resistance is a risk factor for Alzheimer’s disease (AD). Molecular and cellular mechanisms of glucocorticoid resistance in the brain have remained unknown and are potential therapeutic targets. Phosphorylation of glucocorticoid receptors (GR) by brain-derived neurotrophic factor (BDNF) signaling integrates both pathways for remodeli...

Glucocorticoid actions are tailored to the organs and cells responding thanks to complex integration with ongoing signaling mediated by cytokines, hormones, neurotransmitters, and growth factors. Disruption of: (1) the amount of signaling molecules available locally; (2) the timing with other signaling pathways; (3) the post-translational modificat...

Palmitoylation has been involved in several neuropsychiatric and movement disorders for which a dysfunctional signaling of the dopamine D3 receptor (Drd3) is hypothesized. Computational modeling of Drd3's homologue Drd2 has shed some light on the putative role of palmitoylation as a reversible switch for dopaminergic receptor signaling. Drd3 is pre...

Clinical and experimental evidence point to a possible role of cerebrovascular dysfunction in Alzheimer's disease (AD). The 5xFAD mouse model of AD expresses human amyloid precursor protein and presenilin genes with mutations found in AD patients. It remains unknown whether amyloid deposition driven by these mutations is associated with cerebrovasc...

The brain evolved cellular mechanisms for adapting synaptic function to energy supply. This is particularly evident when homeostasis is challenged by stress. Signaling loops between the mitochondria and synapses scale neuronal connectivity with bioenergetics capacity. A biphasic “inverted U shape” response to the stress hormone glucocorticoids is d...

Significance Stress-related disorders are prevalent worldwide, but the pathophysiology of these disorders and specific therapeutic targets remain elusive. Two hypothetical frameworks show great promise: decreased neurotrophic support and decreased responsiveness to glucocorticoids. Our study shows that the glucocorticoid receptor is a prominent tar...

Neuro-vascular rearrangement occurs in brain disorders, including epilepsy. Platelet-derived growth factor receptor beta (PDGFRβ) is a marker of perivascular pericytes, although parenchymal reactivity is described. Whether PDGFRβ(+) cell reorganization occurs in regions of neuro-vascular dysplasia associated with seizures is unknown. We used brain...

Well-defined as signaling hormones for the programming of cell type-specific and context-dependent gene expression signatures, glucocorticoids control experience-driven allostasis. One unifying model is that glucocorticoids help maintaining the integrity and plasticity of cellular networks in changing environments through the mobilization of cellul...

Neurotrophins are synthetized as precursors (proneurotrophins) with a N-terminal prodomain and a C-terminal mature domain. Classically, neurotrophins must be cleaved off their prodomains to be operational. That is to promote neuronal and non-neuronal cell survival, growth and differentiation via rapid signaling routes and long lasting changes in ge...

If the engram of long-term memory is encoded by structural changes of neuronal circuits, they are expected to be present at distant time points after learning, to be specific of circuits activated by learning, and sensitive to behavioral contingencies. In this review we present new concepts that emerged from in vivo imaging studies that tracked the...

The brain is shaped by experience and activity to modulate learning and a wide number of innate and adaptive behaviors. Neural circuits are constantly changing by modifying synapses, which are created and eliminated throughout life. The number and efficacy of synapses undergo dynamic changes in response to experience and neuronal activity. Synapse...

Abnormal glucocorticoid and neurotrophin signaling has been implicated in numerous psychiatric disorders. However, the impact of neurotrophic signaling on glucocorticoid receptor (GR)-dependent gene expression is not understood. We therefore examined the impact of brain-derived neurotrophic factor (BDNF) signaling on GR transcriptional regulatory f...

Abnormal glucocorticoid and neurotrophin signaling have been implicated in numerous psychiatric disorders. However, the impact of neurotrophic signaling on glucocorticoid receptor (GR)-dependent gene expression is not understood. We therefore examined the impact of brain-derived neurotrophic factor (BDNF) signaling on GR transcriptional regulatory...

Excessive glucocorticoid exposure during chronic stress causes synapse loss and learning impairment. Under normal physiological conditions, glucocorticoid activity oscillates in synchrony with the circadian rhythm. Whether and how endogenous glucocorticoid oscillations modulate synaptic plasticity and learning is unknown. Here we show that circadia...

Neurotrophins are potent regulators of synaptic plasticity and memory formation and storage in the brain. Changes in the levels or activities of neurotrophins and their cognate receptors are common in many neurodegenerative and neuropsychiatric disorders. Deficiency in neurotrophic activity leads to neuronal vulnerability, whereas gain of neurotrop...

One hypothesis to account for the onset and severity of neurological disorders is the loss of trophic support. Indeed, changes in the levels and activities of brain-derived neurotrophic factor (BDNF) occur in numerous neurodegenerative and neuropsychiatric diseases. A deficit promotes vulnerability whereas a gain of function facilitates recovery by...

15 chapters on protein phosphorylation and human health written by expert scientists. Covers most important research hot points, such as Akt, AMPK and mTOR. Bridges the basic protein phosphorylation pathways with human health and diseases. Detailed and comprehensive text with excellent figure illustration.

Regulation of the hypothalamic-pituitary-adrenal (HPA) axis is critical for adaptation to environmental changes. The principle regulator of the HPA axis is corticotrophin-releasing hormone (CRH), which is made in the parventricular nucleus and is an important target of negative feedback by glucocorticoids. However, the molecular mechanisms that reg...

Mitogen-activated protein kinase (MAPK) signaling influences a variety of neuronal properties, including structural characteristics such as spine density, and physiological features like long-term potentiation. Spatiotemporal control of MAPK signaling is crucial to generate specific changes in neuronal physiology. However, while many studies have c...

The refinement of neural circuits during development depends on a dynamic process of branching of axons and dendrites that leads to synapse formation and connectivity. The neurotrophin brain-derived neurotrophic factor (BDNF) is essential for the outgrowth and activity-dependent remodeling of axonal arbors in vivo. However, the mechanisms that tran...

Glucocorticoids (GCs) display both protective and destructive effects in the nervous system. In excess, GCs produce neuronal damage after stress or brain injury; however, the neuroprotective effects of adrenal steroids also have been reported. The mechanisms that account for the positive actions are not well understood. Here we report that GCs can...

Familial essential tremor (ET), the most common inherited movement disorder, is generally transmitted as an autosomal dominant trait. A genome-wide scan for ET revealed one major locus on chromosome 3q13. Here, we report that the Ser9Gly variant in the dopamine D3 receptor gene (DRD3), localized on 3q13.3, is associated and cosegregates with famili...

The neurotrophins-nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), NT-3 and NT-4-represent a family of proteins essential for neuronal survival and plasticity. Each neurotrophin can signal through two different transmembrane receptors, Trk receptor tyrosine kinases and the p75 neurotrophin receptor, the first member of the TNF r...

Pleiotropic G proteins are essential for the action of hormones and neurotransmitters and are activated by stimulation of G protein-coupled receptors (GPCR), which initiates heterotrimer dissociation of the G protein, exchange of GDP for GTP on its Galpha subunit and activation of effector proteins. Regulator of G protein signaling (RGS) proteins r...

Protein phosphorylation is crucial for regulating synaptic transmission. We describe a novel mechanism for the phosphorylation of the GABA(A) receptor, which mediates fast inhibition in the brain. A protein copurified and coimmunoprecipitated with the phosphorylated receptor alpha1 subunit; this receptor-associated protein was identified by purific...

The C-terminus domain of G protein-coupled receptors confers a functional cytoplasmic interface involved in protein association. By screening a rat brain cDNA library using the yeast two-hybrid system with the C-terminus domain of the dopamine D(3) receptor (D(3)R) as bait, we characterized a new interaction with the PDZ domain-containing protein,...

To identify proteins interacting with the C-terminal cytoplasmic tail of the dopamine D(3) receptor (D(3)R), we used the two-hybrid system to screen a rat brain cDNA library. We isolated three partial cDNAs encoding, respectively, for the MUPP1 multi-PDZ protein, for the N-terminal region of radixin, for GIPC and for a 160-amino acid open reading f...