It is concluded that presynaptic activity-dependent release of adenosine, through activation of A 2A receptors, facilitates BDNF modulation of synaptic transmission at hippocampal synapses.

Neurogenesis in the dentate gyrus occurs throughout adult mammalian life and is essential for proper hippocampal function. Early in their development, adult-born neurons express homomeric ␣7-containing nicotinic acetylcholine receptors (␣7-nAChRs) and receive direct cholinergic innervation. We show here that functional ␣7-nAChRs are necessary for normal survival, maturation, and integration of adult-born neurons in the dentate gyrus. Stereotaxic retroviral injection into the dentate gyrus of wild-type and ␣7-knock-out (␣7KO) male and female mice was used to label and birthdate adult-born neurons for morphological and electrophysiological measures; BrdU (5-bromo-2-deoxyuridine) injections were used to quantify cell survival. In ␣7KO mice, we find that adult-born neurons develop with truncated, less complex dendritic arbors and display GABAergic postsynaptic currents with immature kinetics. The neurons also have a prolonged period of GABAergic depolarization characteristic of an immature state. In this condition, they receive fewer spontaneous synaptic currents and are more prone to die during the critical period when adult-born neurons are normally integrated into behaviorally relevant networks. Even those adult-born neurons that survive the critical period retain long-term dendritic abnormalities in ␣7KO mice. Interestingly, local infection with retroviral constructs to knockdown ␣7-mRNA mimics the ␣7KO phenotype, demonstrating that the relevant ␣7-nAChR signaling is cell autonomous. The results indicate a profound role for ␣7-nAChRs in adult neurogenesis and predict that ␣7-nAChR loss will cause progressive impairment in hippocampal circuitry and function over time as fewer neurons are added to the dentate gyrus and those that are added integrate less well.

The signaling mechanisms that choreograph the assembly of the highly asymmetric pre-and postsynaptic structures are still poorly defined. Using synaptosome fractionation, immunostaining, and coimmunoprecipitation, we found that Celsr3 and Vangl2, core components of the planar cell polarity (PCP) pathway, are localized at developing glutamatergic synapses and interact with key synaptic proteins. Pyramidal neurons from the hippocampus of Celsr3 knockout mice exhibit loss of ∼50% of glutamatergic synapses, but not inhibitory synapses, in culture. Wnts are known regulators of synapse formation, and our data reveal that Wnt5a inhibits glutamatergic synapses formed via Celsr3. To avoid affecting earlier developmental processes, such as axon guidance, we conditionally knocked out Celsr3 in the hippocampus 1 week after birth. The CA1 neurons that lost Celsr3 also showed a loss of ∼50% of glutamatergic synapses in vivo without affecting the inhibitory synapses assessed by miniature excitatory postsynaptic current (mEPSC) and electron microscopy. These animals displayed deficits in hippocampus-dependent behaviors in adulthood, including spatial learning and memory and fear conditioning. In contrast to Celsr3 conditional knockouts, we found that the conditional knockout of Vangl2 in the hippocampus 1 week after birth led to a large increase in synaptic density, as evaluated by mEPSC frequency and spine density. PCP signaling is mediated by multiple core components with antagonizing functions. Our results document the opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation.Celsr3 | Vangl2 | glutamatergic | synapse formation G lutamatergic synapses, the predominant excitatory synapses in the brain, are asymmetric cell-cell junctions formed from distinct pre-and postsynaptic components involving highly organized complexes of hundreds of proteins across the 20-nm synaptic cleft (1, 2). The signaling pathway that directly assembles these asymmetric protein complexes has not been well understood. Understanding mechanisms of glutamatergic synapse formation will provide important insights into the function and plasticity as well as dysfunction of glutamatergic synapses, which underlie numerous nervous system disorders.Many epithelial tissues show planar cell polarity, the global asymmetry of cellular and tissue morphology and/or structure along the tissue plane (3, 4). The conserved core planar cell polarity (PCP) components, Frizzled, Dishevelled, Diego, Prickle, Vang(l), and Flamingo (Fmi)/Celsr, form asymmetric complexes at the cadherin-mediated adherens junctions that connect neighboring epithelial cells (3, 4). Recent studies suggest that mutations of some components of the PCP signaling pathway, Celsr3/Fmi and Vangl2, affect GABAergic circuit development in zebrafish retina, GABAergic motoneuron synapse development in Caenorhabditis elegans, and hippocampal/cortical glutamatergic and GABAergic synapse formation (5-11). PCP components are critical regulators of neuronal migration and axon guidance, which take p...

SUMMARY A critical feature of neural networks is that they balance excitation and inhibition to prevent pathological dysfunction. How this is achieved is largely unknown, though deficits in the balance contribute to many neurological disorders. We show here that a microRNA (miR-101) is a key orchestrator of this essential feature, shaping the developing network to constrain excitation in the adult. Transient early blockade of miR-101 induces long-lasting hyper-excitability and persistent memory deficits. Using target-site blockers in vivo, we identify multiple developmental programs regulated in parallel by miR-101 to achieve balanced networks. Repression of one target, NKCC1, initiates the switch in GABA signaling, limits early spontaneous activity, and constrains dendritic growth. Kif1a and Ank2 are targeted to prevent excessive synapse formation. Simultaneous de-repression of these three targets completely phenocopies major dysfunctions produced by miR-101 blockade. Our results provide new mechanistic insight into brain development and suggest novel candidates for therapeutic intervention.

The immunological response in the brain is crucial to overcome neuropathological events. Some inflammatory mediators, such as the immunoregulatory cytokine interleukin-6 (IL-6) affect neuromodulation and may also play protective roles against various noxious conditions. However, the fundamental mechanisms underlying the long-term effects of IL-6 in the brain remain unclear. We now report that IL-6 increases the expression and function of the neuronal adenosine A 1 receptor, with relevant consequences to synaptic transmission and neuroprotection. IL-6-induced amplification of A 1 receptor function enhances the responses to readily released adenosine during hypoxia, enables neuronal rescue from glutamate-induced death, and protects animals from chemically induced convulsing seizures. Taken together, these results suggest that IL-6 minimizes the consequences of excitotoxic episodes on brain function through the enhancement of endogenous adenosinergic signaling.

The lateral mobility of surface receptors can define the signaling properties of a synapse and rapidly change synaptic function. Here we use single-particle tracking with Quantum Dots to follow nicotinic acetylcholine receptors (nAChRs) on the surface of chick ciliary ganglion neurons in culture. We find that both heteropentameric ␣3-containing receptors (␣3*-nAChRs) and homopentameric ␣7-containing receptors (␣7-nAChRs) access synaptic domains by lateral diffusion. They have comparable mobilities and display Brownian motion in extrasynaptic space but are constrained and move more slowly in synaptic space. The two receptor types differ in the nature of their synaptic restraints. Disruption of lipid rafts, PDZ-containing scaffolds, and actin filaments each increase the mobility of ␣7-nAChRs in synaptic space while collapse of microtubules has no effect. The opposite is seen for ␣3*-nAChRs where synaptic mobility is increased only by microtubule collapse and not the other manipulations. Other differences are found for regulation of ␣3*-nAChR and ␣7-nAChR mobilities in extrasynaptic space. Most striking are effects on the immobile populations of ␣7-nAChRs and ␣3*-nAChRs. Disruption of either lipid rafts or PDZ scaffolds renders half of the immobile ␣3*-nAChRs mobile without changing the proportion of immobile ␣7-nAChRs. Similar results were obtained with chick sympathetic ganglion neurons, though regulation of receptor mobility differed in at least one respect from that seen with ciliary ganglion neurons. Control of nAChR lateral mobility, therefore, is determined by mechanisms that are domain specific, receptor subtype dependent, and cell-type constrained. The outcome is a system that could tailor nicotinic signaling capabilities to specific needs of individual locations.

Nicotinic mechanisms acting on the hippocampus influence attention, learning, and memory and constitute a significant therapeutic target for many neurodegenerative, neurological, and psychiatric disorders. Here, we report that brain-derived neurotrophic factor (BDNF) (1-100 ng/ml), a member of the neurotrophin gene family, rapidly decreases ␣7 nicotinic acetylcholine receptor responses in interneurons of the hippocampal CA1 stratum radiatum. Such effect is dependent on the activation of the TrkB receptor and involves the actin cytoskeleton; noteworthy, it is compromised when the extracellular levels of the endogenous neuromodulator adenosine are reduced with adenosine deaminase (

Título: El desarrollo de la alianza terapéutica y la aparición de rupturas en la Alianza. Resumen: Objetivos: Este estudio evaluó el desarrollo de la alianza terapéutica y la aparición de rupturas de alianzas, en una muestra de pacientes con diferentes diagnósticos y resultados terapéuticos. Diseño: Se analizaron los datos longitudinales de 38 díadas terapéuticas que recibieran terapia cognitivo-conductual. La muestra incluyó a casos de abandonos, así como casos exitosos y no exitosos. La muestra incluyó a casos con trastornos del Eje I y Eje II. Método: Al final de cada sesión, los pacientes evaluaron la alianza mediante el Inventario de Alianza de Terapéutica (WAI). Seis jueces entrenados en la observación de los marcadores de ruptura de alianza con un sistema de observación de rupturas, codificaran 201 sesiones terapéuti-cas grabadas en vídeo. Se aplicaran modelos estadísticos longitudinales a los datos. Resultados: Se encontró que el patrón de desarrollo de la alianza de los casos de éxito era diferente de la de los casos sin éxito y abandonos. En media, los pacientes con trastornos de la personalidad iniciaran la terapia con una menor puntuación en el WAI que disminuyó con el tiempo, mientras que los pacientes con trastornos del Eje I iniciaran la terapia con una mayor puntuación en el WAI que aumentó con el tiempo. Palabras clave: dDesarrollo de la alianza terapéutica; rupturas en la alianza, trastornos del Eje I; trastornos del Eje II. Abstract:Objectives: This study evaluated the development of the therapeutic alliance and the emergence of alliance ruptures, in a sample of patients with different diagnosis and different therapeutic outcome. Design: We examined the longitudinal data of 38 therapeutic dyads receiving cognitive-behavioural therapy, including dropouts as well as successful and unsuccessful cases. The sample included cases with Axis I and Axis II disorders. Method: At the end of each session, patients evaluated the alliance using the Working Alliance Inventory (WAI). Six judges trained in the observation of alliance rupture markers with an observational system of ruptures, rated 201 videotaped sessions. Longitudinal statistical models were applied to the data. Results: We found that the pattern of alliance development of successful cases was different from the unsuccessful and dropouts cases. In addition on average, patients with personality disorders began therapy with a lower WAI score that decreased over time, whereas patients with Axis-I disorders began therapy with a higher WAI score that increased over time.