Sigma-1 receptors (-1Rs) are endoplasmic reticulum resident chaperone proteins implicated in many physiological and pathological processes in the CNS. A striking feature of -1Rs is their ability to interact and modulate a large number of voltage-and ligand-gated ion channels at the plasma membrane. We have reported previously that agonists for -1Rs potentiate NMDA receptor (NMDAR) currents, although the mechanism by which this occurs is still unclear. In this study, we show that in vivo administration of the selective -1R agonists (ϩ)-SKF 10,047 [2S-(2␣,6␣,11R*]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propenyl)-2,6-methano-3-benzazocin-8-ol hydrochloride (N-allylnormetazocine) hydrochloride], PRE-084 (2-morpholin-4-ylethyl 1-phenylcyclohexane-1-carboxylate hydrochloride), and (ϩ)-pentazocine increases the expression of GluN2A and GluN2B subunits, as well as postsynaptic density protein 95 in the rat hippocampus. We also demonstrate that -1R activation leads to an increased interaction between GluN2 subunits and -1Rs and mediates trafficking of NMDARs to the cell surface. These results suggest that -1R may play an important role in NMDAR-mediated functions, such as learning and memory. It also opens new avenues for additional studies into a multitude of pathological conditions in which NMDARs are involved, including schizophrenia, dementia, and stroke.

Homeostatic processes are believed to contribute to the stability of neuronal networks that are perpetually influenced by Hebbian forms of synaptic plasticity. Whereas the rules governing the targeting and trafficking of AMPA and NMDA subtypes of glutamate receptors during rapid Hebbian LTP have been extensively studied, those that are operant during homeostatic forms of synaptic strengthening are less well understood. Here, we used biochemical, biophysical, and pharmacological approaches to investigate glutamate receptor regulation during homeostatic synaptic plasticity. We show in rat organotypic hippocampal slices that prolonged network silencing induced a robust surface upregulation of GluA2-lacking AMPARs, not only at synapses, but also at extrasynaptic dendritic and somatic regions of CA1 pyramidal neurons. We also detected a shift in NMDAR subunit composition that, in contrast to the cell-wide surface delivery of GluA2-lacking AMPARs, occurred exclusively at synapses. The subunit composition and subcellular distribution of AMPARs and NMDARs are therefore distinctly regulated during homeostatic synaptic plasticity. Thus, because subunit composition dictates key channel properties, such as agonist affinity, gating kinetics, and calcium permeability, the homeostatic synaptic process transcends the simple modulation of synaptic strength by also regulating the signaling and integrative properties of central synapses.

Huntington disease (HD) is an inherited neurodegenerative disorder caused by a mutation in the huntingtin gene. The onset of symptoms is preceded by synaptic dysfunction. Homeostatic synaptic plasticity (HSP) refers to processes that maintain the stability of networks of neurons, thought to be required to enable new learning and cognitive flexibility. One type of HSP is synaptic scaling, in which the strength of all of the synapses onto a cell increases or decreases following changes in the cell’s level of activity. Several pathways implicated in synaptic scaling are dysregulated in HD, including brain-derived neurotrophic factor (BDNF) and calcium signaling. Here, we investigated whether HSP is disrupted in cortical neurons from an HD mouse model. We treated cultured cortical neurons from wild-type (WT) FVB/N or YAC128 HD mice with tetrodotoxin (TTX) for 48 h to silence action potentials and then recorded miniature excitatory postsynaptic currents. In WT cultures, these increased in both amplitude and frequency after TTX treatment, and further experiments showed that this was a result of insertion of AMPA receptors and formation of new synapses, respectively. Manipulation of BDNF concentration in the culture medium revealed that BDNF signaling contributed to these changes. In contrast to WT cortical neurons, YAC128 cultures showed no response to action potential silencing. Strikingly, we were able to restore the TTX-induced changes in YAC128 cultures by treating them with pridopidine, a drug which enhances BDNF signaling through stimulation of the sigma-1 receptor (S1R), and with the S1R agonist 3-PPP. These data provide evidence for disruption of HSP in cortical neurons from an HD mouse model that is restored by stimulation of S1R. Our results suggest a potential new direction for developing therapy to mitigate cognitive deficits in HD.

Huntington's disease (HD) is a hereditary neurodegenerative disorder of typically middle-aged onset for which there is no disease-modifying treatment. Caudate and putamen medium-sized spiny projection neurons (SPNs) most severely degenerate in HD. However, it is unclear why mutant huntingtin protein (mHTT) is preferentially toxic to these neurons or why symptoms manifest only relatively late in life. mHTT interacts with numerous neuronal proteins. Likewise, multiple SPN cellular processes have been described as altered in various HD models. Among these, altered neuronal Ca influx and intracellular Ca handling feature prominently and are addressed here. Specifically, we focus on extrasynaptic NMDA-type glutamate receptors, endoplasmic reticulum IP3 receptors, and mitochondria. As mHTT is expressed throughout development, compensatory processes will likely be mounted to mitigate any deleterious effects. Although some compensations can lessen mHTT's disruptive effects, others-such as upregulation of the ER-refilling store-operated Ca channel response-contribute to pathogenesis. A causation-based approach is therefore necessary to decipher the complex sequence of events linking mHTT to neurodegeneration, and to design rational therapeutic interventions. With this in mind, we highlight evidence, or lack thereof, that the above alterations in Ca handling occur early in the disease process, clearly interact with mHTT, and show disease-modifying potential when reversed in animals.

Huntington's disease (HD) is a fatal, inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene. Altered cortical glutamate release onto striatal spiny projection neurons (SPN) is thought to contribute to pathological synaptic dysfunction in HD; however, the direction of this change is controversial and underlying mechanisms uncertain.We used the YAC128 mouse model of Huntington's disease, expressing the full-length genomic human HTT DNA with 128 repeats, to investigate this question. Here we show that in YAC128 cortical-striatal co-cultures, individual cortical terminals release vesicles onto SPNs at an increased rate compared to wild-type (WT) when action potentials (AP) are blocked with tetrodotoxin (TTX), whereas the release rate is higher in WT than YAC128 cultures when APs are intact. Further, we report increased frequency of miniature excitatory postsynaptic currents (mEPSCs) during the stage of rapid synaptogenesis in vitro for YAC128 cortical cultures, which can be explained by increased spontaneous Ca 2+ released from presynaptic endoplasmic reticulum (ER) stores. Experiments in which axonal bouton Ca 2+ was directly imaged (in TTX) with a synapsin-tagged GCaMP construct revealed higher cytosolic Ca 2+ concentrations and more frequent axonal Ca 2+ waves in YAC128 cultures. Conversely, in the absence of TTX, axonal boutons showed more frequent, larger amplitude Ca 2+ events in WT cortical cultures.Releasing ER Ca 2+ into the cytoplasm with low dose ryanodine, which we believe mimics YAC128 presynaptic Ca 2+ conditions, reduced the amplitude of these AP-dependent Ca 2+ events in WT but not YAC128 boutons. Low dose ryanodine similarly reduced the amplitude of cortical-evoked glutamate release in the striatum of WT, but not YAC128 mouse-derived brain slices. Together, our results demonstrate a shift toward increased spontaneous, and reduced