KCC2 expression promotes the termination of cortical interneuron migration in a voltage-sensitive calcium-dependent manner

The molecular mechanisms controlling the termination of cortical interneuron migration are unknown. Here, we demonstrate that, prior to synaptogenesis, migrating interneurons change their responsiveness to ambient GABA from a motogenic to a stop signal. We found that, during migration into the cortex, ambient GABA and glutamate initially stimulate the motility of interneurons through both GABA(A) and AMPA/NMDA receptor activation. Once in the cortex, upregulation of the potassium-chloride cotransporter KCC2 is both necessary and sufficient to reduce interneuron motility through its ability to reduce membrane potential upon GABA(A) receptor activation, which decreases the frequency of spontaneous intracellular calcium transients initiated by L-type voltage-sensitive calcium channel (VSCC) activation. Our results suggest a mechanism whereby migrating interneurons determine the relative density of surrounding interneurons and principal cells through their ability to sense the combined extracellular levels of ambient glutamate and GABA once GABA(A) receptor activation becomes hyperpolarizing

Neurogenin2 regulates the initial axon guidance of cortical pyramidal neurons projecting medially to the corpus callosum

<p>Abstract</p> <p>Background</p> <p>The formation of the mammalian central nervous system requires the establishment of complex neural circuits between a diverse array of neuronal subtypes. Here we report that the proneural transcription factor Neurogenin2 (Ngn2) is crucial for the proper specification of cortical axon projections.</p> <p>Results</p> <p>The genetic loss of Ngn2 in mice results in fewer callosal axons projecting towards the midline as well as abnormal midline crossing. shRNA-mediated knockdown of Ngn2 revealed its cell-autonomous requirement for the proper projection of axons from layer 2/3 pyramidal neurons to the midline <it>in vivo</it>. We found that the acute loss of Ngn2 <it>in vivo </it>induces the axon of superficial layer 2/3 neurons to project laterally towards aberrant cortical and subcortical targets.</p> <p>Conclusions</p> <p>These and previous results demonstrate that Ngn2 is required for the coordinated specification of cardinal features defining the phenotype of cortical pyramidal neurons, including their migration properties, dendritic morphology and axonal projection.</p

Position and time specify the migration of a pioneering population of olfactory bulb interneurons

We defined the cellular mechanisms for genesis, migration, and differentiation of the initial population of olfactory bulb (OB) interneurons. This cohort of early generated cells, many of which become postmitotic on embryonic day (E) 14.5, differentiates into a wide range of mature OB interneurons by postnatal day (P) 21, and a substantial number remains in the OB at P60. Their precursors autonomously acquire a distinct identity defined by their position in the lateral ganglionic eminence (LGE). The progeny migrate selectively to the OB rudiment in a pathway that presages the rostral migratory stream. After arriving in the OB rudiment, these early generated cells acquire cellular and molecular hallmarks of OB interneurons. Other precursors – including those from the medial ganglionic eminence (MGE) and OB – fail to generate neuroblasts with similar migratory capacity when transplanted to the LGE. The positional identity and migratory specificity of the LGE precursors is rigidly established between E12.5 and E14.5. Thus, the pioneering population of OB interneurons is generated from spatially and temporally determined LGE precursors whose progeny uniquely recognize a distinct migratory trajectory

Genetic mechanisms specifying cortical connectivity: Let's makesome projections together

Great neuroanatomists of the twentieth century recognized that the cerebral cortex of mammals is the single most complex structure of the central nervous system both in terms of neuronal diversity and connectivity. Understanding the cellular and molecular mechanisms specifying the afferent and efferent connectivity in the neocortex may seem like a daunting task. However, recent technical advances have greatly improved our ability to (1) profile gene expression of neuronal populations isolated based on their connectional properties, (2) manipulate gene expression in specific neuronal populations, and (3) visualize their axonal projections in vivo. These new tools are revolutionizing our ability to identify the molecular mechanisms patterning afferent and efferent cortical projections

The CAMKK2-AMPK kinase pathway mediates the synaptotoxic effects of Aβ oligomers through Tau phosphorylation

Amyloid-β 1-42 (Aβ42) oligomers are synaptotoxic for excitatory cortical and hippocampal neurons and might play a role in early stages of Alzheimer's disease (AD) progression. Recent results suggested that Aβ42 oligomers trigger activation of AMP-activated kinase (AMPK), and its activation is increased in the brain of patients with AD. We show that increased intracellular calcium [Ca²⁺](i) induced by NMDA receptor activation or membrane depolarization activates AMPK in a CAMKK2-dependent manner. CAMKK2 or AMPK overactivation is sufficient to induce dendritic spine loss. Conversely, inhibiting their activity protects hippocampal neurons against synaptotoxic effects of Aβ42 oligomers in vitro and against the loss of dendritic spines observed in the human APP(SWE,IND)-expressing transgenic mouse model in vivo. AMPK phosphorylates Tau on KxGS motif S262, and expression of Tau S262A inhibits the synaptotoxic effects of Aβ42 oligomers. Our results identify a CAMKK2-AMPK-Tau pathway as a critical mediator of the synaptotoxic effects of Aβ42 oligomers

Progressive Decrease of Mitochondrial Motility during Maturation of Cortical Axons In Vitro and In Vivo

The importance of mitochondria for neuronal function is evident by the large number of neurodegenerative diseases that have been associated with a disruption of mitochondrial function or transport. Mitochondria are essential for proper biological function as a result of their ability to produce ATP through oxidative phosphorylation, buffer cytoplasmic calcium, regulate lipid biosynthesis, and trigger apoptosis. Efficient transport of mitochondria is thought to be particularly important in neurons in light of their compartmentalization, length of axonal processes, and high-energy requirements). However, the majority of these results were obtained using short-term, in vitro neuronal culture models, and very little is currently known about mitochondrial dynamics in mature axons of the mammalian CNS in vitro or in vivo. Furthermore, recent evidence has demonstrated that mitochondrial immobilization at specific points along the axon, such as presynaptic boutons, play critical roles in axon morphogenesis [4, 5]. We report that as cortical axons mature, motility of mitochondria (but not other cargoes) is dramatically reduced and this coincides with increased localization to presynaptic sites. We also demonstrate using photo-conversion that in vitro mature axons display surprisingly limited long-range mitochondrial transport. Finally, using in vivo two-photon microscopy in anesthetized or awake-behaving mice, we document for the first time that mitochondrial motility is also remarkably low in distal cortical axons in vivo. These results argue that mitochondrial immobilization and presynaptic localization are important hallmarks of mature CNS axons both in vitro and in vivo

SRGAP2 and Its Human-Specific Paralog Co-Regulate the Development of Excitatory and Inhibitory Synapses.

The proper function of neural circuits requires spatially and temporally balanced development of excitatory and inhibitory synapses. However, the molecular mechanisms coordinating excitatory and inhibitory synaptogenesis remain unknown. Here we demonstrate that SRGAP2A and its human-specific paralog SRGAP2C co-regulate the development of excitatory and inhibitory synapses in cortical pyramidal neurons in vivo. SRGAP2A promotes synaptic maturation, and ultimately the synaptic accumulation of AMPA and GABAA receptors, by interacting with key components of both excitatory and inhibitory postsynaptic scaffolds, Homer and Gephyrin. Furthermore, SRGAP2A limits the density of both types of synapses via its Rac1-GAP activity. SRGAP2C inhibits all identified functions of SRGAP2A, protracting the maturation and increasing the density of excitatory and inhibitory synapses. Our results uncover a molecular mechanism coordinating critical features of synaptic development and suggest that human-specific duplication of SRGAP2 might have contributed to the emergence of unique traits of human neurons while preserving the excitation/inhibition balance

Temperature Imaging using Quadriwave Shearing Interferometry. Applications in Thermoplasmonics

International audienceThe use of illuminated gold nanoparticles as ideal nanosources of heat is the basis of numerous research activities and applications in physics, chemistry, biology and medicine. This field defines the area recently named Thermoplasmonics [1]. In most of the activities related to Thermoplasmonics, probing the temperature at the vicinity of the metal nanoparticles is not an easy task. In this context, we recently developed a novel optical microscopy technique, named TIQSI, aimed at mapping the temperature around plasmonic nanoparticles [2]. The approach is based on the measure of the thermal-induced variation of the refractive index surrounding the sources of heat. The TIQSI technique cumulates all the advantages a thermal microscopy technique may require: i) high resolution (diffraction limited), ii) high readout rate (less than one image per second), iii) high temperature sensitivity (<1°C), iv) large accessible temperature range, v) temperature can be measured without fluorescence labelling or any other kind of thermal probe, v) no need to use sophisticated devices such as heterodyne detection, acousto-optic modulator, spectrometer, etc, like previous thermal imaging techniques. In this presentation, we will first introduce the TIQSI technique, its principle and capabilities. We will then present several recent applications made it possible by this new thermal imaging technique. In particular, we shall explain how this technique have been already used to quantitatively measure the absorption cross section of gold nanoparticles [3] and graphene sheets, how it can be used to map the temperature in real time in living cells [4], how it can help to design temperature distributions at will at the microscale using gold nanoparticles [5,7], and how it can be used to investigate thermal-induced phenomena in hydro- dynamics and phase transitions [6]

New insights into the molecular mechanisms specifying neuronal polarity in vivo

The polarization of axon and dendrites underlies the ability of neurons to integrate and transmit information in the brain. Important progress has been made towards the identification of the molecular mechanisms regulating neuronal polarization using primarily in vitro approaches such as dissociated culture of rodent hippocampal neurons. The predominant view emerging from this paradigm is that neuronal polarization is initiated by intrinsic activation of signaling pathways underlying the initial break in neuronal symmetry that precedes the future asymmetric growth of the axon. Recent evidence shows that (i) axon-dendrite polarization is specified when neurons engage migration in vivo, (ii) a kinase pathway defined by LKB1and SAD-kinases (Par4/Par1 dyad) is required for proper neuronal polarization in vivo and that (iii) extracellular cues can play an instructive role during neuronal polarization. Here, we review some of these recent results and highlight future challenges in the field including the determination of how extracellular cues control intracellular responses underlying neuronal polarization in vivo

Linearity improvement of VCSELs based radio over fiber systems utilizing digital predistortion

The article proposes a Digital Predistortion (DPD) methodology that substantially meliorates the linearity of limited range Mobile Front Haul links for the extant Long-Term Evolution (LTE) and future (5G) networks. Specifically, the DPD is employed to Radio over Fiber links that contrive of Vertical Cavity Surface Emitting Lasers (VCSELs) working at 850 nm. Both, Memory and Generalized Memory Polynomial models are implied to Single Mode (SM) and Multi-Mode (MM) VCSELs respectively. The effectiveness of the proposed DPD methodology is analyzed in terms of Normalized Mean Square Error, Normalized Magnitude, Normalized phase and Adjacent Channel Power Ratio. The demonstration has been carried out with a complete (Long Term Evolution) LTE frame of 10 ms having 5 MHz bandwidth with 64-QAM modulation configuration. Additionally, the effectuality of the proposed DPD technique is evaluated for varying levels of input power and link lengths. The experimental outcomes signify the novel capability of the implied DPD methodology for different link lengths to achieve higher system linearization