Acetylcholine prioritises direct synaptic inputs from entorhinal cortex to CA1 by differential modulation of feedforward inhibitory circuits.

Acetylcholine release in the hippocampus plays a central role in the formation of new memory representations. An influential but largely untested theory proposes that memory formation requires acetylcholine to enhance responses in CA1 to new sensory information from entorhinal cortex whilst depressing inputs from previously encoded representations in CA3. Here, we show that excitatory inputs from entorhinal cortex and CA3 are depressed equally by synaptic release of acetylcholine in CA1. However, feedforward inhibition from entorhinal cortex exhibits greater depression than CA3 resulting in a selective enhancement of excitatory-inhibitory balance and CA1 activation by entorhinal inputs. Entorhinal and CA3 pathways engage different feedforward interneuron subpopulations and cholinergic modulation of presynaptic function is mediated differentially by muscarinic M3 and M4 receptors, respectively. Thus, our data support a role and mechanisms for acetylcholine to prioritise novel information inputs to CA1 during memory formation

Author Correction: Acetylcholine prioritises direct synaptic inputs from entorhinal cortex to CA1 by differential modulation of feedforward inhibitory circuits

Acetylcholine release in the hippocampus plays a central role in the formation of new memory representations. An influential but largely untested theory proposes that memory formation requires acetylcholine to enhance responses in CA1 to new sensory information from entorhinal cortex whilst depressing inputs from previously encoded representations in CA3. Here, we show that excitatory inputs from entorhinal cortex and CA3 are depressed equally by synaptic release of acetylcholine in CA1. However, feedforward inhibition from entorhinal cortex exhibits greater depression than CA3 resulting in a selective enhancement of excitatory-inhibitory balance and CA1 activation by entorhinal inputs. Entorhinal and CA3 pathways engage different feedforward interneuron subpopulations and cholinergic modulation of presynaptic function is mediated differentially by muscarinic M3 and M4 receptors, respectively. Thus, our data support a role and mechanisms for acetylcholine to prioritise novel information inputs to CA1 during memory formation

Functional impact of interacting protein on kainate receptors: NeCaB1 and NeTo proteins

Los receptores de glutamato son los responsables de mediar la transmisión sináptica rápida en el sistema nervioso central. Esta familia de receptores está formada por tres tipos: los receptores de AMPA, NMDA y kainato. Entre estos, los receptores de kainato son los menos conocidos desde el punto de vista fisiológico. Con el objetivo de revelar la función de estos receptores, nosotros estamos interesados en descubrir el interactoma de los receptores de kainato. En este trabajo nos hemos centrado en la interacción con la proteína NeCaB1, la cual se halló en un ensayo de doble híbrido y las proteínas Neto1-2. NeCaB1 se une al dominio C-terminal de los receptores de kainato que contienen la subunidad GluK5. Esta interacción desplaza los receptores de kainato hacia la superficie celular e incrementa la afinidad de dichos receptores, todo ello operado por la disponibilidad de calcio. Así, NeCaB1 puede controlar la clase de receptores de kainato que se encuentran en la superficie celular en respuesta la actividad neuronal, lo que podría constituir un nuevo modo de plasticidad homeostática. Por otra parte, las proteínas Neto1 y Neto2 son capaces de interactuar con los tres tipos mayoritarios de receptores de kainato (GluK1-3), pero el grado y signo modulación depende de la composición de los receptores de kainato. También hemos observado que Neto1 y Neto2 son los responsables de las lentas cinéticas de las respuestas sinápticas mediadas por receptores de kainato, mientras que su localización en las sinapsis está mediada por la subunidad GluK5. Este trabajo pone de manifiesto como las proteínas que interactúan con los receptores de kainato pueden explicar el complejo funcionamiento de estos receptores

Synaptic targeting of kainate receptors

When native and recombinant kainate receptors (KARs) are compared, there is a mismatch in several of their functional properties. While both generate currents, synaptic responses mediated by KARs have rarely observed in cultured hippocampal neurons. The recent discovery of auxiliary proteins for KARs, such as Netos, offers an explanation for these discrepancies. We found that the GluK5 KAR subunit and the ancillary proteins, Neto1 and Neto2, are not expressed by hippocampal neurons in culture. Therefore, we used this model to directly test whether these proteins are required for the synaptic localization of KARs. Transfection of GluK4, GluK5, Neto1, or Neto2 into hippocampal neurons was associated with the appearance of synaptic KAR-mediated EPSCs. However, GluK4 or GluK5 alone produced synaptic activity in a significant proportion of cells and with reliable event frequency. While neurons expressing GluK4 or GluK5 subunits displayed synaptic responses with rapid kinetics, the expression of Neto proteins conferred these synaptic responses with their characteristic slow onset and decay rates. These data reveal some requirements for KAR targeting to the synapse, indicating a fundamental role of high affinity KAR subunits in this process.This work was supported by grants to J.L. from the Spanish MICINN (BFU2006-07138 and BFU2011-24084), CONSOLIDER (CSD2007-00023), and Prometeo/2011/086. J.P. was supported by a PhD fellowship from the Gobierno Vasco and by the Generalitat Valenciana. The Instituto de Neurociencias is a “Center of Excellence Severo Ochoa.”Peer reviewe

In vitro modelling of Alzheimer's disease: Degeneration and cell death induced by viral delivery of amyloid and tau

12 p., 7 figures and referencesWith increasing life expectancy, Alzheimer's disease (AD) and other dementias pose an increasing and as yet unresolved health problem. A variety of cellular models of AD has helped to decipher some key aspects of amyloid and tau related degeneration. The initial approach of extracellular applications of synthetic peptides has now been replaced by the introduction of amyloid precursor protein (APP) and tau genes. In the present study adenoviral transductions were exploited for gene delivery into primary rat hippocampal and dorsal root ganglion (DRG) cultures to enable comparative and mechanistic studies at the cellular level and subsequent drug testing. Time lapse experiments revealed a different pattern of cell death: apoptotic-like for APP whereas tau positive cells joined and formed clusters. Mutated human APP or tau expression caused accelerated neuronal damage and cell death (cf. EGFP: -50% for APP at 5days; -40% for tau at 3days). This reduction in viability was preceded by decreased excitability, monitored via responses to depolarising KCl-challenges in Ca 2+ imaging experiments. Additionally, both transgenes reduced neurite outgrowth in DRG neurones. Treatment studies confirmed that APP induced-damage can be ameliorated by β- and γ-secretase inhibitors (providing protection to 60-100% of control levels), clioquinol (80%) and lithium (100%); while anti-aggregation treatments were beneficial for tau-induced damage (60-90% recovery towards controls). Interestingly, caffeine was the most promising drug candidate for therapeutic intervention with high efficacy in both APP (77%) and tau-induced models (72% recovery). Overall, these cellular models offer advantages for mechanistic studies and target identification in AD and related disorders.SS was in part supported by a Sixth Century studentship.Peer reviewe