Retrograde signaling by endocannabinoids (eCBs) mediates a widely expressed form of long-term depression at excitatory and inhibitory synapses (eCB-LTD), involving a reduction in neurotransmitter ...release. In the hippocampus, eCB-LTD occurs at interneuron (IN)-pyramidal cell (PC) synapses (I-LTD), and its induction requires a presynaptic reduction of cAMP/PKA signaling resulting from minutes of type 1 cannabinoid receptor (CB1R) activation. Although repetitive activity of glutamatergic synapses initiates the eCB mobilization required for I-LTD, it is unclear whether CB1R-containing GABAergic terminals are passive targets of eCBs or whether they actively contribute to induction. Here, we show that the minutes-long induction period for I-LTD may serve as a window to integrate associated spontaneous activity in the same IN receiving the retrograde eCB signal. Indeed, reducing spontaneous IN firing blocked I-LTD, which could be rescued with extra stimulation of inhibitory afferents. Moreover, cell pair recordings showed that a single IN expressed LTD onto a PC only if it was active during eCB signaling. Several methods of disrupting presynaptic Ca²⁺ dynamics all blocked I-LTD, strongly suggesting that IN spikes regulate I-LTD by raising Ca²⁺ at the nerve terminal. Finally, inhibiting the Ca²⁺-activated phosphatase, calcineurin, fully blocked I-LTD, but blocking another phosphatase did not. Our findings support a model where both CB1R signaling and IN activity shift the balance of kinase and phosphatase activity in the presynaptic terminal to induce I-LTD.
The type-1 cannabinoid receptor (CB
R) is widely expressed in excitatory and inhibitory nerve terminals, and by suppressing neurotransmitter release, its activation modulates neural circuits and ...brain function. While the interaction of CB
R with various intracellular proteins is thought to alter receptor signaling, the identity and role of these proteins are poorly understood. Using a high-throughput proteomic analysis complemented with an array of in vitro and in vivo approaches in the mouse brain, we report that the C-terminal, intracellular domain of CB
R interacts specifically with growth-associated protein of 43 kDa (GAP43). The CB
R-GAP43 interaction occurs selectively at mossy cell axon boutons, which establish excitatory synapses with dentate granule cells in the hippocampus. This interaction impairs CB
R-mediated suppression of mossy cell to granule cell transmission, thereby inhibiting cannabinoid-mediated anti-convulsant activity in mice. Thus, GAP43 acts as a synapse type-specific regulatory partner of CB
R that hampers CB
R-mediated effects on hippocampal circuit function.
La inclusión educativa en Chile es un tema que ha cobrado relevancia en la última década, y que de manera paulatina ha logrado posicionarse en la agenda pública nacional, no antes de enfrentar ...dificultades por los múltiples significados que adquiere el concepto de inclusión y el cual aún no existe un consenso amplio. A partir de un enfoque analítico-crítico de la literatura y políticas educativas en materia de inclusión en el caso chileno, damos a conocer los principales enfoques que se desarrollan en la actualidad y las perspectivas de mejora que plantean unos de sus principales actores, como son los formadores de formadores. Entre los principales cambios demandados se pretende generar un perfil de competencias que debiese tener el profesorado para atender la diversidad, destacando el trabajo colaborativo, la responsabilidad profesional para analizar críticamente las políticas educativas, el diseño e implementación de estrategias didácticas inclusivas que generen climas bien tratantes y democráticos en las aulas, entre otras. Finalmente, se entregan recomendaciones para su correcta implementación en la formación inicial docente, en especial las tendientes a modificaciones reales en las mallas curriculares de todas las carreras pedagógicas.Doi: 10.21703/rexe.20212043castillo19
Gap junctions constitute the only form of synaptic communication between neurons in the inferior olive (IO), which gives rise to the climbing fibers innervating the cerebellar cortex. Although its ...exact functional role remains undetermined, electrical coupling was shown to be necessary for the transient formation of functional compartments of IO neurons and to underlie the precise timing of climbing fibers required for cerebellar learning. So far, most functional considerations assume the existence of a network of permanently and homogeneously coupled IO neurons. Contrasting this notion, our results indicate that coupling within the IO is highly variable. By combining tracer-coupling analysis and paired electrophysiological recordings, we found that individual IO neurons could be coupled to a highly variable number of neighboring neurons. Furthermore, a given neuron could be coupled at remarkably different strengths with each of its partners. Freeze-fracture analysis of IO glomeruli revealed the close proximity of glutamatergic postsynaptic densities to connexin 36-containing gap junctions, at distances comparable to separations between chemical transmitting domains and gap junctions in goldfish mixed contacts, where electrical coupling was shown to be modulated by the activity of glutamatergic synapses. On the basis of structural and molecular similarities with goldfish mixed synapses, we speculate that, rather than being hardwired, variations in coupling could result from glomerulus-specific long-term modulation of gap junctions. This striking heterogeneity of coupling might act to finely influence the synchronization of IO neurons, adding an unexpected degree of complexity to olivary networks.
An abundant presynaptic protein, α-synuclein, is centrally involved in the pathogenesis of Parkinson's disease. However, conflicting data exist about the normal function of α-synuclein, possibly ...because α-synuclein is redundant with the very similar β-synuclein. To investigate the functions of synucleins systematically, we have now generated single- and double-knockout (KO) mice that lack α- and/or β-synuclein. We find that deletion of synucleins in mice does not impair basic brain functions or survival. We detected no significant changes in the ultrastructure of synuclein-deficient synapses, in short- or long-term synaptic plasticity, or in the pool size or replenishment of recycling synaptic vesicles. However, protein quantitations revealed that KO of synucleins caused selective changes in two small synaptic signaling proteins, complexins and 14-3-3 proteins. Moreover, we found that dopamine levels in the brains of double-KO but not single-KO mice were decreased by ≈20%. In contrast, serotonin levels were unchanged, and dopamine uptake and release from isolated nerve terminals were normal. These results show that synucleins are not essential components of the basic machinery for neurotransmitter release but may contribute to the long-term regulation and/or maintenance of presynaptic function.
Presynaptic autoreceptors modulate transmitter release at many synapses. At the mossy fiber to CA3 pyramidal cell (mf-CA3) synapse, two types of glutamatergic autoreceptors have been identified: ...transmitter release is reportedly suppressed by metabotropic glutamate receptors (mGluRs) and augmented by kainate receptors (KARs). However, the net effect of these autoreceptors when activated by endogenous glutamate is unknown. Here, we show that during low-frequency mossy fiber stimulation, glutamate acting through presynaptic mGluRs substantially suppresses transmitter release. However, using similar recording conditions, we find that presynaptic KARs are insufficient to facilitate transmitter release over a wide range of mossy fiber stimulus frequencies, indicating that the uniquely robust mf-CA3 short-term plasticity is KAR independent. Furthermore, we report that actions generally attributed to presynaptic KARs are likely due to activation of recurrent CA3 network activity. Thus, negative feedback via presynaptic mGluRs is the dominant mode of glutamatergic autoregulation at the mf-CA3 synapse.
Neurotransmitter release probability (Pr) largely determines the dynamic properties of synapses. While much is known about the role of presynaptic proteins in transmitter release, their specific ...contribution to synaptic plasticity is unclear. One such protein, tomosyn, is believed to reduce Pr by interfering with the SNARE complex formation. Tomosyn is enriched at hippocampal mossy fiber-to-CA3 pyramidal cell synapses (MF-CA3), which characteristically exhibit low Pr, strong synaptic facilitation, and pre-synaptic protein kinase A (PKA)-dependent long-term potentiation (LTP). To evaluate tomosyn’s role in MF-CA3 function, we used a combined knockdown (KD)-optogenetic strategy whereby presynaptic neurons with reduced tomosyn levels were selectively activated by light. Using this approach in mouse hippocampal slices, we found that facilitation, LTP, and PKA-induced potentiation were significantly impaired at tomosyn-deficient synapses. These findings not only indicate that tomosyn is a key regulator of MF-CA3 plasticity but also highlight the power of a combined KD-optogenetic approach to determine the role of presynaptic proteins.
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•MF-CA3 synaptic plasticity can be reliably assessed using optogenetics•Combined KD-optogenetic strategy enables selective activation of manipulated neurons•MF-CA3 short-term plasticity is drastically reduced in tomosyn-deficient synapses•Increased basal Pr at tomosyn-deficient synapses occludes MF-CA3 LTP
Hippocampal mossy fiber synapses exhibit a characteristically low basal release probability, enabling strong activity-dependent facilitation. Using a combination of shRNA and optogenetics, Ben-Simon et al. show that tomosyn—a negative regulator of SNARE proteins—critically regulates basal release probability, thereby contributing to presynaptic mossy fiber plasticity.
•Dissociated donor vascular cells in neural transplants form vessels.•Donor-derived vessels fuse with host vessels to circulate blood in neural grafts.•Including vascular cells in transplants at ...stroke sites is essential for graft growth.
Neural precursor cells (NPCs) transplanted into the adult neocortex generate neurons that synaptically integrate with host neurons, supporting the possibility of achieving functional tissue repair. However, poor survival and functional neuronal recovery of transplanted NPCs greatly limits engraftment. Here, we test the hypothesis that combining blood vessel-forming vascular cells with neuronal precursors improves engraftment. By transplanting mixed embryonic neocortical cells into adult mice with neocortical strokes, we show that transplant-derived neurons synapse with appropriate targets while donor vascular cells form vessels that fuse with the host vasculature to perfuse blood within the graft. Although all grafts became vascularized, larger grafts had greater contributions of donor-derived vessels that increased as a function of their distance from the host-graft border. Moreover, excluding vascular cells from the donor cell population strictly limited graft size. Thus, inclusion of vessel-forming vascular cells with NPCs is required for more efficient engraftment and ultimately for tissue repair.
Synucleins are a vertebrate-specific family of abundant neuronal proteins. They comprise three closely related members, alpha -, beta -, and gamma -synuclein. alpha -Synuclein has been the focus of ...intense attention since mutations in it were identified as a cause for familial Parkinson's disease. Despite their disease relevance, the normal physiological function of synucleins has remained elusive. To address this, we generated and characterized alpha beta gamma -synuclein knockout mice, which lack all members of this protein family. Deletion of synucleins causes alterations in synaptic structure and transmission, age-dependent neuronal dysfunction, as well as diminished survival. Abrogation of synuclein expression decreased excitatory synapse size by similar to 30% both in vivo and in vitro, revealing that synucleins are important determinants of presynaptic terminal size. Young synuclein null mice show improved basic transmission, whereas older mice show a pronounced decrement. The late onset phenotypes in synuclein null mice were not due to a loss of synapses or neurons but rather reflect specific changes in synaptic protein composition and axonal structure. Our results demonstrate that synucleins contribute importantly to the long-term operation of the nervous system and that alterations in their physiological function could contribute to the development of Parkinson's disease.
El presente estudio centró su atención en el tipo de liderazgo que se ejerce dentro de un proyecto de Liceo Bicentenario, reconocido por especialistas educativos como uno de los 100 liceos públicos ...con mejores desempeños académicos a nivel nacional. Bajo un enfoque cualitativo-interpretativo, con un diseño de estudio de caso, se aplicaron entrevistas en profundidad al profesorado y miembros del equipo directivo que, junto a la revisión documental interna del centro, nos entregaron los siguientes resultados. Las diversas prácticas asociadas a procesos de excelencia pedagógicos que logra el profesorado con sus estudiantes responden a una cultura de mejora constante, influenciada por un estilo de liderazgo pedagógico y distribuido que impulsa todo el equipo directivo. Destaca que este tipo de cultura ha generado un clima de confianza y un trabajo de autoeficacia colectiva que es reconocido como sello identitario por toda la comunidad educativa y que hace que el profesorado se sienta orgulloso de pertenecer a la institución. Esta situación contribuye a un constante desarrollo profesional que permite aumentar sus dominios disciplinares y pedagógicos. Se destacan también las mentorías voluntarias entre pares y una eficiente gestión curricular de líderes intermedios. Finalmente, podemos mencionar que este proyecto de liceo bicentenario es reconocido por sus actores con la característica de inclusivo y no selectivo, apartándose de la idea original que se tiene de este tipo de proyectos educativos.
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