Maxim Cazorla

French Institute of Health and Medical Research | Inserm · Institut de Neurosciences de la Timone

Connectomics has revolutionized our understanding of brain function by emphasizing the importance of neural networks and their topographical organization. Corticostriatal circuits, which play a critical role in cognition and emotion, follow a precise topographic architecture essential for integrating and processing cortical information within the b...

In chemical synapses undergoing high frequency stimulation, vesicle components can be retrieved from the plasma membrane via a clathrin-independent process called activity-dependent bulk endocytosis (ADBE). Alix (ALG-2-interacting protein X/PDCD6IP) is an adaptor protein binding to ESCRT and endophilin-A proteins which is required for clathrin-inde...

In chemical synapses undergoing high frequency stimulation, vesicle components can be retrieved from the plasma membrane via a clathrin-independent process called activity dependent bulk endocytosis (ADBE). Alix (ALG-2 interacting protein X)/ PDCD6IP) is an adaptor protein binding to ESCRT and endophilin-A proteins and thereby driving deformation a...

In the central nervous system, neurons are organized in specific neural networks with distinct electrical patterns, input integration capacities, and intracellular dynamics. In order to better understand how neurons process information, it is crucial to keep the complex organization of brain circuits. However, performing subcellular investigations...

Abstract Studying intracellular dynamics in neurons is crucial to better understand how brain circuits communicate and adapt to environmental changes. In neurons, axonal secretory vesicles underlie various functions from growth during development to plasticity in the mature brain. Similarly, transport of mitochondria, the power plant of the cell, r...

Huntington's disease (HD), a devastating neurodegenerative disorder, strongly affects the corticostriatal network, but the contribution of pre- and postsynaptic neurons in the first phases of disease is unclear due to difficulties performing early subcellular investigations in vivo. Here, we have developed an on-a-chip approach to reconstitute an H...

Background: Enhancing the brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signalling pathway has been repeatedly suggested as a promising therapeutic strategy for restoring cognitive impairments in various murine models of Alzheimer's disease (AD) [1]. Evidence indicates that synthetic TrkB agonists prevent, attenuate...

Most of the cellular or molecular studies in HD used so far separated cultures of striatal or cortical neurons. However, in the brain these neurons are connected and form a particular network that is defective in HD. The polarised nature of neurons and the size and density of synapses complicates the manipulation and visualisation of specific event...

Unlabelled: Cocaine exposure alters brain-derived neurotrophic factor (BDNF) expression in the brain. BDNF signaling through TrkB receptors differentially modulates cocaine self-administration, depending on the brain regions involved. In the present study, we determined how brain-wide inhibition of TrkB signaling affects cocaine intake, the motiva...

Current therapies for treating movement disorders such as Parkinson's disease are effective but limited by undesirable and intractable side effects. Developing more effective therapies will require better understanding of what causes basal ganglia dysregulation and why medication-induced side effects develop. Although basal ganglia have been extens...

Structural plasticity in the adult brain is essential for adaptive behavior. We have found a remarkable anatomical plasticity in the basal ganglia of adult mice that is regulated by dopamine D2 receptors (D2Rs). By modulating neuronal excitability, striatal D2Rs bidirectionally control the density of direct pathway collaterals in the globus pallidu...

Unlabelled: Several lines of evidence indicate that brain-derived neurotrophic factor (BDNF) plays a key role as a central pronociceptive modulator of pain, acting through postsynaptic TrkB receptors that trigger intracellular signaling cascades leading to central sensitization. The overall aim of this study was to investigate to what extent BDNF...

Structural plasticity in the adult brain is essential for adaptive behaviors and is thought to contribute to a variety of neurological and psychiatric disorders. Medium spiny neurons of the striatum show a high degree of structural plasticity that is modulated by dopamine through unknown signaling mechanisms. Here, we demonstrate that overexpressio...

The neurotrophin brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) have emerged as key mediators in the pathophysiology of several mood disorders, including anxiety and depression. However, therapeutic compounds that interact with TrkB receptors have been difficult to develop. Using a combination of struc...

By interacting with trkB receptors, brain-derived neurotrophic factor (BDNF) triggers various signalling pathways responsible for neurone survival, differentiation and modulation of synaptic transmission. Numerous reports have implicated BDNF and trkB in the pathogenesis of various central nervous system affections and in cancer, thus representing...

Brain-derived neurotrophic factor (BDNF) is expressed in the mammalian pituitary gland, in both the anterior and intermediate lobes, where its functional significance is unknown. Melanotrope cells in the intermediate pituitary lobe of the amphibian Xenopus laevis also produce BDNF, which co-exists in secretory granules with α-melanophore-stimulatin...

Supplementary information (0.04 MB DOC)

Cells systems for the analysis of recombinant and neuronal TrkB receptors. (A) Representative fluorescence photomicrographs of TetOn-rhTrkB inducible cells following an overnight incubation with (middle panel) or without (left panel) doxycycline and confocal TrkB immunofluorescence in mouse cortical neurons (right panel). Scale bar, 55 µm. (B) West...

Pharmacology of recombinant and neuronal TrkB receptor using KIRA-ELISA. (A,B) KIRA-ELISA concentration-response curves for BDNF, NT-3 and NGF in TetOn-rhTrkB cells and in cultured cortical neurons. Results are expressed as mean ± s.e.m. of raw absorbance read at 450 nm in six independent experiments performed in triplicate. (C,D) Inhibition of Trk...

BDNF-induced neuronal necrosis is prevented by cyclotraxin-B. Cyclotraxin-B prevents BDNF-induced neurons death through a NMDA-independent pathway. Cortical neurons were treated with cyclotraxin-B (200 nM), BDNF (4 nM), NMDA (200 µM) or MK-801 (1 µM), as indicated. Data are mean ± s.e.m. (octuples, n = 6) expressed in percentage of control. ***P<0....

Cyclotraxin-B inhibits eIF4E phosphorylation in cortical neurons. Cortical neurons were exposed to cyclotraxin-B, K252a and BDNF, as indicated. Phosphorylation of eIF4E was quantified by immunoblots using anti-phospho and anti-total-eIF4E antibodies. A representative western-blot is shown here. (0.33 MB TIF)

Cyclotraxin-B does not compete with [125I]-BDNF binding to recombinant nor to neuronal TrkB receptors. Effect of unlabeled BDNF (closed circle), NT-3 (closed triangle), NGF (closed square), peptide L2-8 (open triangle) and cyclotraxin-B (open circle) on [125I]-BDNF binding to recombinant and neuronal TrkB receptors. Adherent cells were pre-incubate...

Basal activity of TrkB receptors in absence of BDNF. (A) Absence of endogenous BDNF in cultured cortical neurons. Neuronal cells were incubated 24 hours with a neutralizing anti-BDNF antibody before treatment with cyclotraxin-B. KIRA-ELISA analysis revealed no significant difference in cyclotraxin-B inhibition with or without pretreatment with anti...

Protocol for in vivo KIRA-ELISA analysis after intravenous injection. (A) Adult mice received two i.v. injections of saline buffer, tat-empty or tat-cyclotraxin-B (1). Brains were then sliced at three levels (bregma 0.90 mm: caudate putamen/nucleus accumbens level; bregma −1.60 mm: dorsal hippocampus level; bregma −2.70 mm: ventral hippocampus leve...

Tat-cyclotraxin-B inhibits both recombinant and neuronal TrkB receptors similarly to cyclotraxin-B. Characterization of TrkB inhibition by tat-cyclotraxin-B using KIRA-ELISA assays in TetOn-rhTrkB cells and in cortical neurons. Increasing concentrations of tat-empty and tat-cyclotraxin-B were added to the cells for 30 min prior to treatment with or...

In the last decades, few mechanistically novel therapeutic agents have been developed to treat mental and neurodegenerative disorders. Numerous studies suggest that targeting BDNF and its TrkB receptor could be a promising therapeutic strategy for the treatment of brain disorders. However, the development of potent small ligands for the TrkB recept...