Cannabinoid receptor activation reduces TNFα-Induced surface localization of AMPAR-type glutamate receptors and excitotoxicity
Introduction
Control over normal neuronal glutamatergic signaling depends largely on the localization of AMPARs on synaptic and extrasynaptic plasma membrane (Malinow and Malenka, 2002). This balance can be disrupted during CNS injury or disease when the inflammatory response is initiated and the population of AMPARs on neuronal plasma membrane increases dramatically, potentiating END (reviewed in Leonoudakis et al., 2004, Pickering et al., 2005). We previously characterized TNFα as a powerful glial-derived instigator of AMPAR trafficking to the plasma membrane (Beattie et al., 2002, Stellwagen et al., 2005). The presence of TNFα in the CNS is required for synaptic development (Stellwagen and Malenka, 2006), but the increased TNFα concentrations induced following infection or injury (Nemeth et al., 1997) contribute to END (Lock et al., 1999, Nagatsu et al., 2000, New et al., 1998, Perry et al., 2001, Shohami et al., 1999, Szelenyi, 2001). Several groups attribute this toxicity to long-term, translation-dependent apoptotic signaling pathways (Fontaine et al., 2002, Reimann-Philipp et al., 2001, Yang et al., 2002, Zhao et al., 2001, Zou and Crews, 2005). However, TNFα also induces a rapid (within 15 min) increase in surface expression of AMPARs (Beattie et al., 2002, Ogoshi et al., 2005, Stellwagen et al., 2005) which are calcium permeable and principally localized extrasynaptically (Leonoudakis et al., 2008). Additionally, acute neurotrauma increases surface expression of calcium permeable AMPARs composed of GluR1 subunits (Grooms et al., 2000, Grossman et al., 1999, Sanchez et al., 2001, Ying et al., 1998), and potentiates neuronal excitotoxicity (Feldmeyer et al., 1999, Oguro et al., 1999). Together, these studies suggest that TNFα-induced AMPAR surface expression may be a mechanism contributing to the early stages of END. Agents which decrease TNFα-induced AMPAR surface expression may reduce excitotoxicity in neurons and our previous studies suggest the use of cannabinoid receptor agonists may serve as a potential pharmacological intervention (Abood et al., 2001).
The cannabinoid receptor system is found in hippocampal neurons (Leterrier et al., 2006, Mackie, 2007, McDonald et al., 2007) and protects against excitotoxicity (Kim et al., 2006, Marsicano et al., 2003, Shen and Thayer, 1998, Shen and Thayer, 1999). Activation of the G-protein-coupled CB1 cannabinoid receptor initiates complex signaling cascades and leads to the hyperpolarization of neuronal membranes by increasing potassium and decreasing calcium conductance (Howlett, 2002). Our current results suggest a novel neuroprotective mechanism under the control of CB1, namely the reduction of excessive AMPAR surface expression caused by TNFα. We have used hippocampal culture systems to examine AMPAR surface expression and neuron survival after KA-induced excitotoxicity while exogenously applying TNFα. Our results demonstrate that CB1 activation prevents the TNFα-induced increase in surface GluR1-containing AMPARs and protects neurons from TNFα potentiated excitotoxic stress.
Section snippets
Preparation of hippocampal cultures
Mixed hippocampal neuron cultures were prepared from E18 rat pups as previously described (Beattie et al., 2002). Briefly, hippocampi of embryonic day 18 (E18) Sprague Dawley rats were removed, digested with papain, and dissociated by trituration. Neurons were plated in Neurobasal medium containing B27 supplement and Glutamax (Invitrogen) on coverslips or plastic plates coated with poly-d-lysine. After cell attachment (3–4 h), the medium was replaced. Three days later, an equal volume of
Expression of GluR1 and CB1 receptors on hippocampal neurons
In hippocampal neurons, GluR1-containing AMPARs colocalize with postsynaptic markers on somatic and dendritic plasma membranes (Beattie et al., 2002, Stellwagen et al., 2005) and CB1 has been detected in plasma membrane and cytosolic compartments of somato-dendritic regions as well as on axonal plasma membranes (Leterrier et al., 2006, McDonald et al., 2007). To confirm surface expression of CB1 in or near postsynaptic membrane in our hippocampal neuron cultures we have used immunofluorescence
Discussion
Our data is supportive of the hypothesis that activation of CB1 decreases TNFα-induced surface expression of AMPARs and protects against END in hippocampal cultures. CB1, AMPARs, and TNFα receptors are all expressed in dendrites in our cultured hippocampal neurons where intracellular signaling between CB1 and TNFα receptors may compete to regulate AMPAR trafficking (Marsicano et al., 2003) as suggested in studies of cortical pyramidal neurons (Hill et al., 2007, Kim et al., 2006) and spinal
Acknowledgments
MEA is supported by grants from the NIH (DA09978, DA05274) and by The Forbes Norris ALS Center. EB is supported by grants from the NIH (MH067931 and NS038079) as well as by The Forbes Norris ALS Center, the California Pacific Medical Center Research Institute, and ALSA (starter grant 766). We thank Robert Kim and Sean Prasad for excellent technical assistance with the live imaging experiments. We thank Dr. Patricia Reggio (University of North Carolina, Greensboro) and Dr. Herb Seltzman (RTI)
References (64)
- et al.
Activation of the CB(1) cannabinoid receptor protects cultured mouse spinal neurons against excitotoxicity
Neurosci. Lett.
(2001) - et al.
The impact of excitotoxic blockade on the evolution of injury following combined mechanical and hypoxic insults in primary rat neuronal culture
Neurobiol. Dis.
(2004) - et al.
Tumor necrosis factor-alpha induces cFOS and strongly potentiates glutamate-mediated cell death in the rat spinal cord
Neurobiol. Dis.
(2001) The cannabinoid receptors
Prostaglandins Other Lipid Mediat.
(2002)- et al.
Calcium-permeable AMPA channels in neurodegenerative disease and ischemia
Curr. Opin. Neurobiol.
(2006) - et al.
HIV-1 Tat induces neuronal death via tumor necrosis factor-alpha and activation of non-N-methyl-D-aspartate receptors by a NFkappaB-independent mechanism
J. Biol. Chem.
(1998) - et al.
Tumor necrosis-factor-alpha (TNF-alpha) induces rapid insertion of Ca2+-permeable alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)/kainate (Ca-A/K) channels in a subset of hippocampal pyramidal neurons
Exp. Neurol.
(2005) - et al.
Extrasynaptic membrane trafficking regulated by GluR1 serine 845 phosphorylation primes AMPA receptors for long-term potentiation
J. Biol. Chem.
(2006) - et al.
The role of TNF and its receptors in Alzheimer's disease
Neurobiol. Aging
(2001) - et al.
CB1 cannabinoid receptors in amphibian spinal cord: relationships with some nociception markers
J. Chem. Neuroanat.
(2002)
Dual role of tumor necrosis factor alpha in brain injury
Cytokine Growth Factor Rev.
Cytokines and the central nervous system
Brain Res. Bull.
Cannabinoids reduce cAMP levels in the striatum of freely moving rats: an in vivo microdialysis study
Brain Res.
Metabotropic glutamate receptor activation causes a rapid redistribution of AMPA receptors
Neuropharmacology
Increased densities of AMPA GluR1 subunit proteins and presynaptic mossy fiber sprouting in the fascia dentata of human hippocampal epilepsy
Brain Res.
TNF alpha potentiates glutamate neurotoxicity by inhibiting glutamate uptake in organotypic brain slice cultures: neuroprotection by NF kappa B inhibition
Brain Res.
Assessment of cell viability in primary neuronal cultures
Curr. Protoc. Neurosci.
Control of synaptic strength by glial TNFalpha
Science
Modulator effects of interleukin-1beta and tumor necrosis factor-alpha on AMPA-induced excitotoxicity in mouse organotypic hippocampal slice cultures
J. Neurosci.
Calcium-permeable AMPA-kainate receptors in fusiform cerebellar glial cells
Science
Motor neurons are selectively vulnerable to AMPA/kainate receptor-mediated injury in vitro
J. Neurosci.
Tumor necrosis factor-alpha potentiates glutamate neurotoxicity in human fetal brain cell cultures
Dev. Neurosci.
Endocannabinoid-mediated synaptic plasticity in the CNS
Annu. Rev. Neurosci.
Characterization of the role of microtubule-associated protein 1B in metabotropic glutamate receptor-mediated endocytosis of AMPA receptors in hippocampus
J. Neurosci.
The endocannabinoid system and its therapeutic exploitation
Nat. Rev. Drug Discov.
Neurological dysfunctions in mice expressing different levels of the Q/R site-unedited AMPAR subunit GluR-B
Nat. Neurosci.
Cell death after spinal cord injury is exacerbated by rapid TNF alpha-induced trafficking of GluR2-lacking AMPARs to the plasma membrane
J. Neurosci.
Neurodegenerative and neuroprotective effects of tumor Necrosis factor (TNF) in retinal ischemia: opposite roles of TNF receptor 1 and TNF receptor 2
J. Neurosci.
Activation of D1 dopamine receptors increases surface expression of AMPA receptors and facilitates their synaptic incorporation in cultured hippocampal neurons
J. Neurochem.
Neurotoxic effects of tumor necrosis factor alpha in primary human neuronal cultures are mediated by activation of the glutamate AMPA receptor subtype: implications for AIDS neuropathogenesis
Dev. Neurosci.
Behavioral and histological characterization of unilateral cervical spinal cord contusion injury in rats
J. Neurotrauma
Status epilepticus decreases glutamate receptor 2 mRNA and protein expression in hippocampal pyramidal cells before neuronal death
Proc. Natl. Acad. Sci. U.S.A.
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These authors contributed equally to this work.