Mechanosensitivity extends beyond sensory cells to encompass most neurons in the brain. Here, we explore recent research on the role of integrins, a diverse family of adhesion molecules, as crucial biomechanical sensors translating mechanical forces into biochemical and electrical signals in the brain. The varied biomechanical properties of neuronal integrins, including their force-dependent conformational states and ligand interactions, dictate their specific functions.
View Article and Find Full Text PDFThe distance between Ca2.1 voltage-gated Ca channels and the Ca sensor responsible for vesicle release at presynaptic terminals is critical for determining synaptic strength. Yet, the molecular mechanisms responsible for a loose coupling configuration of Ca2.
View Article and Find Full Text PDFThe relationship between autism spectrum disorder (ASD) and dendritic spine abnormalities is well known, but it is unclear whether the deficits relate to specific neuron types and brain regions most relevant to ASD. Recent genetic studies have identified a convergence of ASD risk genes in deep layer pyramidal neurons of the prefrontal cortex. Here, we use retrograde recombinant adeno-associated viruses to label specifically two major layer V pyramidal neuron types of the medial prefrontal cortex: the commissural neurons, which put the two cerebral hemispheres in direct communication, and the corticopontine neurons, which transmit information outside the cortex.
View Article and Find Full Text PDFIntracellular trafficking of AMPA receptors is a tightly regulated process which involves several adaptor proteins, and is crucial for the activity of excitatory synapses both in basal conditions and during synaptic plasticity. We found that, in rat hippocampal neurons, an intracellular pool of the tetraspanin TSPAN5 promotes exocytosis of AMPA receptors without affecting their internalisation. TSPAN5 mediates this function by interacting with the adaptor protein complex AP4 and Stargazin and possibly using recycling endosomes as a delivery route.
View Article and Find Full Text PDFMol Ther Nucleic Acids
September 2022
Many mutations in autism spectrum disorder (ASD) affect a single allele, indicating a key role for gene dosage in ASD susceptibility. Recently, haplo-insufficiency of , the gene encoding the extracellular matrix receptor β3 integrin, was associated with ASD. Accordingly, knockout (KO) mice exhibit autism-like phenotypes.
View Article and Find Full Text PDFNeuronal differentiation is a complex process whose dysfunction can lead to brain disorders. The development of new tools to target specific steps in the neuronal differentiation process is of paramount importance for a better understanding of the molecular mechanisms involved, and ultimately for developing effective therapeutic strategies for neurodevelopmental disorders. Through their interactions with extracellular matrix proteins, the cell adhesion molecules of the integrin family play essential roles in the formation of functional neuronal circuits by regulating cell migration, neurite outgrowth, dendritic spine formation and synaptic plasticity.
View Article and Find Full Text PDFKinase D interacting substrate of 220 kDa (Kidins220), also known as ankyrin repeat-rich membrane spanning (ARMS), is a transmembrane scaffold protein that participates in fundamental aspects of neuronal physiology including cell survival, differentiation, and synaptic plasticity. The Kidins220 constitutive knockout line displays developmental defects in the nervous and cardiovascular systems that lead to embryonic lethality, which has so far precluded the study of this protein in the adult. Moreover, Kidins220 mRNA is tightly regulated by alternative splicing, whose impact on nervous system physiology has not yet been addressed in vivo.
View Article and Find Full Text PDFAstroglial cells are key to maintain nervous system homeostasis. Neurotrophins are known for their pleiotropic effects on neuronal physiology but also exert complex functions to glial cells. Here, we investigated (i) the signaling competence of mouse embryonic and postnatal primary cortical astrocytes exposed to brain-derived neurotrophic factor (BDNF) and, (ii) the role of kinase D-interacting substrate of 220 kDa (Kidins220), a transmembrane scaffold protein that mediates neurotrophin signaling in neurons.
View Article and Find Full Text PDFEpisodic ataxia type 2 (EA2) is an autosomal dominant neurological disorder characterized by paroxysmal attacks of ataxia, vertigo, and nausea that usually last hours to days. It is caused by loss-of-function mutations in , the gene encoding the pore-forming α subunit of P/Q-type voltage-gated Ca channels. Although pharmacological treatments, such as acetazolamide and 4-aminopyridine, exist for EA2, they do not reduce or control the symptoms in all patients.
View Article and Find Full Text PDFIntegrins are extracellular matrix receptors that mediate biochemical and mechanical bi-directional signals between the extracellular and intracellular environment of a cell thanks to allosteric conformational changes. In the brain, they are found in both neurons and glial cells, where they play essential roles in several aspects of brain development and function, such as cell migration, axon guidance, synaptogenesis, synaptic plasticity and neuro-inflammation. Although there are many successful examples of how regulating integrin adhesion and signaling can be used for therapeutic purposes, for example for halting tumor progression, this is not the case for the brain, where the growing evidence of the importance of integrins for brain pathophysiology has not translated yet into medical applications.
View Article and Find Full Text PDFHomeostatic plasticity refers to the ability of neuronal networks to stabilize their activity in the face of external perturbations. Most forms of homeostatic plasticity ultimately depend on changes in the expression or activity of ion channels and synaptic proteins, which may occur at the gene, transcript, or protein level. The most extensively investigated homeostatic mechanisms entail adaptations in protein function or localization following activity-dependent posttranslational modifications.
View Article and Find Full Text PDFThrough their ability to modulate synaptic transmission, glial cells are key regulators of neuronal circuit formation and activity. Kidins220/ARMS (kinase-D interacting substrate of 220 kDa/ankyrin repeat-rich membrane spanning) is one of the key effectors of the neurotrophin pathways in neurons where it is required for differentiation, survival, and plasticity. However, its role in glial cells remains largely unknown.
View Article and Find Full Text PDFThe purpose of this protocol is to characterize the effect of gene knockdown on presynaptic function within intact neuronal circuits. We describe a workflow on how to combine artificial microRNA (miR)-mediated RNA interference with optogenetics to achieve selective stimulation of manipulated presynaptic boutons in acute brain slices. The experimental approach involves the use of a single viral construct and a single neuron-specific promoter to drive the expression of both an optogenetic probe and artificial miR(s) against presynaptic gene(s).
View Article and Find Full Text PDFBy regulating actin cytoskeleton dynamics, Rho GTPases and their activators RhoGEFs are implicated in various aspects of neuronal differentiation, including dendritogenesis and synaptogenesis. Purkinje cells (PCs) of the cerebellum, by developing spectacular dendrites covered with spines, represent an attractive model system in which to decipher the molecular signaling underlying these processes. To identify novel regulators of dendritic spine morphogenesis among members of the poorly characterized DOCK family of RhoGEFs, we performed gene expression profiling of fluorescence-activated cell sorting (FACS)-purified murine PCs at various stages of their postnatal differentiation.
View Article and Find Full Text PDFEpithelial invagination is a common feature of embryogenesis. An example of invagination morphogenesis occurs during development of the early eye when the lens placode forms the lens pit. This morphogenesis is accompanied by a columnar-to-conical cell shape change (apical constriction or AC) and is known to be dependent on the cytoskeletal protein Shroom3.
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