Clathrin-independent endocytic retrieval of SV proteins mediated by the clathrin adaptor AP-2 at mammalian central synapses

Neurotransmission is based on the exocytic fusion of synaptic vesicles (SVs) followed by endocytic membrane retrieval and the reformation of SVs. Conflicting models have been proposed regarding the mechanisms of SV endocytosis, most notably clathrin/adaptor protein complex 2 (AP-2)-mediated endocytosis and clathrin-independent ultrafast endocytosis. Partitioning between these pathways has been suggested to be controlled by temperature and stimulus paradigm. We report on the comprehensive survey of six major SV proteins to show that SV endocytosis in mouse hippocampal neurons at physiological temperature occurs independent of clathrin while the endocytic retrieval of a subset of SV proteins including the vesicular transporters for glutamate and GABA depend on sorting by the clathrin adaptor AP-2. Our findings highlight a clathrin-independent role of the clathrin adaptor AP-2 in the endocytic retrieval of select SV cargos from the presynaptic cell surface and suggest a revised model for the endocytosis of SV membranes at mammalian central synapses.

Mutations in DISC1 alter IP3R and Voltage-Gated Ca2+ Channel Functioning: Implications for Major Mental Illness

Disrupted in Schizophrenia 1 (DISC1) participates in a wide variety of developmental processes of central neurons. It also serves critical roles that underlie cognitive functioning in adult central neurons. Here we summarize DISC1’s general properties and discuss its use as a model system for understanding major mental illnesses. We then discuss the cellular actions of DISC1 that involve or regulate Ca2+ signaling in adult central neurons. In particular, we focus on the tethering role DISC1 plays in transporting RNA particles containing Ca2+ channel subunit RNAs, including IP3R1, CACNA1C and CACNA2D1, and in transporting mitochondria into dendritic and axonal processes. We also review DISC1’s role in modulating IP3R1 activity within mitochondria-associated ER membrane. Finally, we discuss DISC1-GSK3b signaling that regulates functional expression at voltage-gated Ca2+ channel at central synapses. In each case, DISC1 regulates the movement of molecules that impact Ca2+ signaling in neurons.

Homeostatic regulation of presynaptic NMDA receptor subunit composition modulates action potential driven Ca2+ influx into boutons setting the bandwidth for information transfer

SummaryN-Methyl-D-aspartate receptors (NMDARs) play a pivotal role in both short and long-term plasticity. While the functional role of postsynaptic NMDARs is well established, a framework of presynaptic NMDAR (preNMDAR) function is missing. Differences in subunit composition of preNMDARs are documented at central synapses, raising the possibility that subtype composition plays a role in transmission performance. Here, we use electrophysiological recordings at Schaffer collateral - CA1 synapses and Ca2+ imaging coupled to focal glutamate uncaging at boutons of CA3 pyramidal neurones to reveal two populations of presynaptic NMDARs that contain either the GluN2A or GluN2B subunit. Activation of the GluN2B population decreases action potential (AP)-evoked Ca2+ influx via modulation of small conductance Ca2+-activated K+ channels (SK-channels) while activation of the GluN2A containing population does the opposite. Moreover, the level of functional expression of each receptor population can be homeostatically modified, bidirectionally affecting short-term facilitation during burst firing, thus providing a capacity for a fine adjustment of the presynaptic integration time window and therefore the bandwidth of information transfer.

AZP2006, a new promising treatment for Alzheimer’s and related diseases

Progranulin (PGRN) is a protein with multiple functions including the regulation of neuroinflammation, neuronal survival, neurite and synapsis growth. Although the mechanisms of action of PGRN are currently unknown, its potential therapeutic application in treating neurodegenerative diseases is huge. Thus, strategies to increase PGRN levels in patients could provide an effective treatment. In the present study, we investigated the effects of AZP2006, a lysotropic molecule now in phase 2a clinical trial in Progressive Supranuclear Palsy patients, for its ability to increase PGRN level and promote neuroprotection. We showed for the first time the in vitro and in vivo neuroprotective effects of AZP2006 in neurons injured with Aβ1–42 and in two different pathological animal models of Alzheimer’s disease (AD) and aging. Thus, the chronic treatment with AZP2006 was shown to reduce the loss of central synapses and neurons but also to dramatically decrease the massive neuroinflammation associated with the animal pathology. A deeper investigation showed that the beneficial effects of AZP2006 were associated with PGRN production. Also, AZP2006 binds to PSAP (the cofactor of PGRN) and inhibits TLR9 receptors normally responsible for proinflammation when activated. Altogether, these results showed the high potential of AZP2006 as a new putative treatment for AD and related diseases.

A Multisubcellular Compartment Model of AMPA Receptor Trafficking for Neuromodulation of Hebbian Synaptic Plasticity

Neuromodulation can profoundly impact the gain and polarity of postsynaptic changes in Hebbian synaptic plasticity. An emerging pattern observed in multiple central synapses is a pull–push type of control in which activation of receptors coupled to the G-protein Gs promote long-term potentiation (LTP) at the expense of long-term depression (LTD), whereas receptors coupled to Gq promote LTD at the expense of LTP. Notably, coactivation of both Gs- and Gq-coupled receptors enhances the gain of both LTP and LTD. To account for these observations, we propose a simple kinetic model in which AMPA receptors (AMPARs) are trafficked between multiple subcompartments in and around the postsynaptic spine. In the model AMPARs in the postsynaptic density compartment (PSD) are the primary contributors to synaptic conductance. During LTP induction, AMPARs are trafficked to the PSD primarily from a relatively small perisynaptic (peri-PSD) compartment. Gs-coupled receptors promote LTP by replenishing peri-PSD through increased AMPAR exocytosis from a pool of endocytic AMPAR. During LTD induction AMPARs are trafficked in the reverse direction, from the PSD to the peri-PSD compartment, and Gq-coupled receptors promote LTD by clearing the peri-PSD compartment through increased AMPAR endocytosis. We claim that the model not only captures essential features of the pull–push neuromodulation of synaptic plasticity, but it is also consistent with other actions of neuromodulators observed in slice experiments and is compatible with the current understanding of AMPAR trafficking.

A centronuclear myopathy-causing mutation in dynamin-2 perturbs the actin-dependent structure of dendritic spines leading to excitatory synaptic defects in a murine model of the disease

Dynamin-2 is a large GTP-ase, member of the dynamin superfamily, that regulates membrane remodeling and cytoskeleton dynamics. In the mammalian nervous system dynamin-2 modulates synaptic vesicle (SV)-recycling at the nerve terminals and receptor-trafficking to and from postsynaptic densities (PSDs). Mutations in dynamin-2 cause autosomal dominant centronuclear myopathy (CNM), a congenital neuromuscular disorder characterized by progressive weakness and atrophy of distal skeletal muscles. Cognitive defects have also been reported in dynamin-2-linked CNM patients suggesting a concomitant impairment of the central nervous system. Here we addressed the mechanisms that lead to cognitive defects in dynamin-2-linked CNM using a knock-in mouse model that harbors the p.R465W mutation in dynamin-2, the most common causing CNM. Our results show that these mice exhibit reduced capability to learn and acquire spatial and recognition memory, impaired long-term potentiation of the excitatory synaptic strength and perturbed dendritic spine morphology, which seem to be associated with actin defects. Together, these data reveal for the first time that structural and functional synaptic defects underlie cognitive defects in the CNM context. In addition our results contribute to the still scarce knowledge about the importance of dynamin-2 at central synapses.

Tonic Endocannabinoid Signaling Gates Synaptic Plasticity in Dorsal Raphe Nucleus Serotonin Neurons Through Peroxisome Proliferator-Activated Receptors

Endocannabinoids (eCBs), which include 2-arachidonoylglycerol (2-AG) and anandamide (AEA) are lipid signaling molecules involved in the regulation of an array of behavioral and physiological functions. Released by postsynaptic neurons, eCBs mediate both phasic and tonic signaling at central synapses. While the roles of phasic eCB signaling in modulating synaptic functions and plasticity are well characterized, very little is known regarding the physiological roles and mechanisms regulating tonic eCB signaling at central synapses. In this study, we show that both 2-AG and AEA are constitutively released in the dorsal raphe nucleus (DRN), where they exert tonic control of glutamatergic synaptic transmission onto serotonin (5-HT) neurons. The magnitude of this tonic eCB signaling is tightly regulated by the overall activity of neuronal network. Thus, short term in vitro neuronal silencing or blockade of excitatory synaptic transmission abolishes tonic eCB signaling in the DRn. Importantly, in addition to controlling basal synaptic transmission, this study reveals that tonic 2-AG, but not AEA signaling, modulates synaptic plasticity. Indeed, short-term increase in tonic 2-AG signaling impairs spike-timing dependent potentiation (tLTP) of glutamate synapses. This tonic 2-AG-mediated homeostatic control of DRN glutamate synapses is not signaled by canonical cannabinoid receptors, but by intracellular peroxisome proliferator-activated receptor gamma (PPARγ). Further examination reveals that 2-AG mediated activation of PPARγ blocks tLTP by inhibiting nitric oxide (NO), soluble guanylate cyclase, and protein kinase G (NO/sGC/PKG) signaling pathway. Collectively, these results unravel novel mechanisms by which tonic 2-AG signaling integrates network activities and controls the synaptic plasticity in the brain.

Clathrin-independent endocytic retrieval of SV proteins mediated by the clathrin adaptor AP-2 at mammalian central synapses

Neurotransmission is based on the exocytic fusion of synaptic vesicles (SVs) followed by endocytic membrane retrieval and the reformation of SVs. Conflicting models have been proposed regarding the mechanisms of SV endocytosis, most notably clathrin/ AP-2-mediated endocytosis and clathrin-independent ultrafast endocytosis. Partitioning between these pathways has been suggested to be controlled by temperature and stimulus paradigm. We report on the comprehensive survey of six major SV proteins to show that SV endocytosis in hippocampal neurons at physiological temperature occurs independent of clathrin while the endocytic retrieval of a subset of SV proteins including the vesicular transporters for glutamate and GABA depend on sorting by the clathrin adaptor AP-2. Our findings highlight a clathrin-independent role of the clathrin adaptor AP-2 in the endocytic retrieval of select SV cargos from the presynaptic cell surface and suggest a unified model for the endocytosis of SV membranes at mammalian central synapses.

Oligodendroglial GABAergic Signaling: More Than Inhibition!

GABA is the main inhibitory neurotransmitter in the CNS acting at two distinct types of receptor: ligand-gated ionotropic GABAA receptors and G protein-coupled metabotropic GABAB receptors, thus mediating fast and slow inhibition of excitability at central synapses. GABAergic signal transmission has been intensively studied in neurons in contrast to oligodendrocytes and their precursors (OPCs), although the latter express both types of GABA receptor. Recent studies focusing on interneuron myelination and interneuron-OPC synapses have shed light on the importance of GABA signaling in the oligodendrocyte lineage. In this review, we start with a short summary on GABA itself and neuronal GABAergic signaling. Then, we elaborate on the physiological role of GABA receptors within the oligodendrocyte lineage and conclude with a description of these receptors as putative targets in treatments of CNS diseases.