Picking out the Details of Cerebellar LTD

Cerebellar long-term depression is thought to underlie motor learning and is mediated by internalization of AMPA receptors from the neuronal plasma membrane. In this issue of Neuron, Steinberg et al. provide firm evidence that PICK1 and the C terminus of GluR2 are central to this process by analyzing three different transgenic mice

The Regulation of AMPA Receptor Endocytosis by Dynamic Protein-Protein Interactions

The precise regulation of AMPA receptor (AMPAR) trafficking in neurons is crucial for excitatory neurotransmission, synaptic plasticity and the consequent formation and modification of neural circuits during brain development and learning. Clathrin-mediated endocytosis (CME) is an essential trafficking event for the activity-dependent removal of AMPARs from the neuronal plasma membrane, resulting in a reduction in synaptic strength known as long-term depression (LTD). The regulated AMPAR endocytosis that underlies LTD is caused by specific modes of synaptic activity, most notably stimulation of NMDA receptors (NMDARs) and metabotropic glutamate receptors (mGluRs). Numerous proteins associate with AMPAR subunits, directly or indirectly, to control their trafficking, and therefore the regulation of these protein-protein interactions in response to NMDAR or mGluR signaling is a critical feature of synaptic plasticity. This article reviews the protein-protein interactions that are dynamically regulated during synaptic plasticity to modulate AMPAR endocytosis, focussing on AMPAR binding proteins and proteins that bind the core endocytic machinery. In addition, the mechanisms for the regulation of protein-protein interactions are considered, as well as the functional consequences of these dynamic interactions on AMPAR endocytosis

Oxygen/Glucose deprivation induces a reduction in synaptic AMPA receptors on hippocampal CA3 neurons mediated by mGluR1 and adenosine A3 receptors

Hippocampal CA1 pyramidal neurons are highly sensitive to ischemic damage, whereas neighboring CA3 pyramidal neurons are less susceptible. It is proposed that switching of AMPA receptor (AMPAR) subunits on CA1 neurons during an in vitro model of ischemia, oxygen/glucose deprivation (OGD), leads to an enhanced permeability of AMPARs to Ca2+, resulting in delayed cell death. However, it is unclear whether the same mechanisms exist in CA3 neurons and whether this underlies the differential sensitivity to ischemia. Here, we investigated the consequences of OGD for AMPAR function in CA3 neurons using electrophysiological recordings in rat hippocampal slices. Following a 15 min OGD protocol, a substantial depression of AMPAR-mediated synaptic transmission was observed at CA3 associational/commissural and mossy fiber synapses but not CA1 Schaffer collateral synapses. The depression of synaptic transmission following OGD was prevented by metabotropic glutamate receptor 1 (mGluR1) or A3 receptor antagonists, indicating a role for both glutamate and adenosine release. Inhibition of PLC, PKC, or chelation of intracellular Ca2+ also prevented the depression of synaptic transmission. Inclusion of peptides to interrupt the interaction between GluA2 and PICK1 or dynamin and amphiphysin prevented the depression of transmission, suggesting a dynamin and PICK1-dependent internalization of AMPARs after OGD. We also show that a reduction in surface and total AMPAR protein levels after OGD was prevented by mGluR1 or A3 receptor antagonists, indicating that AMPARs are degraded following internalization. Thus, we describe a novel mechanism for the removal of AMPARs in CA3 pyramidal neurons following OGD that has the potential to reduce excitotoxicity and promote neuroprotectio

Protein interacting with C kinase 1 suppresses invasion and anchorage independent growth of astrocytic tumour cells

Astrocytic tumors are the most common form of primary brain tumor. Astrocytic tumor cells infiltrate the surrounding CNS tissue, allowing them to evade removal upon surgical resection of the primary tumor. Dynamic changes to the actin cytoskeleton are crucial to cancer cell invasion, but the specific mechanisms that underlie the particularly invasive phenotype of astrocytic tumor cells are unclear. Protein interacting with C kinase 1 (PICK1) is a PDZ and BAR domain–containing protein that inhibits actin-related protein 2/3 (Arp2/3)-dependent actin polymerization and is involved in regulating the trafficking of a number of cell-surface receptors. Here we report that, in contrast to other cancers, PICK1 expression is down-regulated in grade IV astrocytic tumor cell lines and also in clinical cases of the disease in which grade IV tumors have progressed from lower-grade tumors. Exogenous expression of PICK1 in the grade IV astrocytic cell line U251 reduces their capacity for anchorage-independent growth, two-dimensional migration, and invasion through a three-dimensional matrix, strongly suggesting that low PICK1 expression plays an important role in astrocytic tumorigenesis. We propose that PICK1 negatively regulates neoplastic infiltration of astrocytic tumors and that manipulation of PICK1 is an attractive possibility for therapeutic intervention

Mechanisms of AMPA receptor endosomal sorting

The regulation of synaptic AMPA receptors (AMPARs) is critical for excitatory synaptic transmission, synaptic plasticity and the consequent formation of neural circuits during brain development and their modification during learning and memory processes. The number of synaptic AMPARs is regulated through endocytosis, exocytosis and endosomal sorting that results in recycling back to the plasma membrane or degradation in the lysosome. Hence, endo-lysosomal sorting is vitally important in maintaining AMPAR expression at the synapse, and the dynamic regulation of these trafficking events is a key component of synaptic plasticity. A reduction in synaptic strength such as in long-term depression (LTD) involves AMPAR sorting to lysosomes to reduce synaptic AMPAR number, whereas long-term potentiation (LTP) involves an increase in AMPAR recycling to increase the number of AMPARs at synapses. Here, we review our current understanding of the endosomal trafficking routes taken by AMPARs, and the mechanisms involved in AMPAR endosomal sorting, focussing on the numerous AMPAR associated proteins that have been implicated in this complex process. We also discuss how these events are dysregulated in brain disorders

Endocytosis and lysosomal degradation of GluA2/3 AMPARs in response to oxygen/glucose deprivation in hippocampal but not cortical neurons

Abstract Global cerebral ischemia results in oxygen and glucose deprivation (OGD) and consequent delayed cell death of vulnerable neurons, with hippocampal CA1 neurons more vulnerable than cortical neurons. Most AMPA receptors (AMPARs) are heteromeric complexes of subunits GluA1/GluA2 or GluA2/GluA3, and the presence of GluA2 renders AMPARs Ca2+-impermeable. In hippocampal CA1 neurons, OGD causes the synaptic expression of GluA2-lacking Ca2+-permeable AMPARs, contributing to toxic Ca2+ influx. The loss of synaptic GluA2 is caused by rapid trafficking of GluA2-containing AMPARs from the cell surface, followed by a delayed reduction in GluA2 mRNA expression. We show here that OGD causes endocytosis, lysosomal targeting and consequent degradation of GluA2- and GluA3-containing AMPARs, and that PICK1 is required for both OGD-induced GluA2 endocytosis and lysosomal sorting. Our results further suggest that GluA1-containing AMPARs resist OGD-induced endocytosis. OGD does not cause GluA2 endocytosis in cortical neurons, and we show that PICK1 binding to the endocytic adaptor AP2 is enhanced by OGD in hippocampal, but not cortical neurons. We propose that endocytosis of GluA2/3, caused by a hippocampal-specific increase in PICK1-AP2 interactions, followed by PICK1-dependent lysosomal targeting, are critical events in determining changes in AMPAR subunit composition in the response to ischaemia

Chitin and carbon nanotube composites as biocompatible scaffolds for neuron growth

Preparation of biocompatible and electrically-conducting chitin nanotube composite scaffold for potential use in implantable electrode for stimulation and repair of neurons.</p

Tau isoform-specific enhancement of L-type calcium current and augmentation of afterhyperpolarization in rat hippocampal neurons

Accumulation of tau is observed in dementia, with human tau displaying 6 isoforms grouped by whether they display either 3 or 4 C-terminal repeat domains (3R or 4R) and exhibit no (0N), one (1N) or two (2N) N terminal repeats. Overexpression of 4R0N-tau in rat hippocampal slices enhanced the L-type calcium (Ca(2+)) current-dependent components of the medium and slow afterhyperpolarizations (AHPs). Overexpression of both 4R0N-tau and 4R2N-tau augmented Ca(V)1.2-mediated L-type currents when expressed in tsA-201 cells, an effect not observed with the third 4R isoform, 4R1N-tau. Current enhancement was only observed when the pore-forming subunit was co-expressed with Ca(V)β3 and not Ca(V)β2a subunits. Non-stationary noise analysis indicated that enhanced Ca(2+) channel current arose from a larger number of functional channels. 4R0N-tau and Ca(V)β3 were found to be physically associated by co-immunoprecipitation. In contrast, the 4R1N-tau isoform that did not augment expressed macroscopic L-type Ca(2+) current exhibited greatly reduced binding to Ca(V)β3. These data suggest that physical association between tau and the Ca(V)β3 subunit stabilises functional L-type channels in the membrane, increasing channel number and Ca(2+) influx. Enhancing the Ca(2+)-dependent component of AHPs would produce cognitive impairment that underlie those seen in the early phases of tauopathies