Caveolin-1 knockout mice exhibit impaired induction of mGluR-dependent long-term depression at CA3-CA1 synapses

Abstract

Group I metabotropic glutamate receptors (mGluR1/5) are important to synaptic circuitry formation during development and to forms of activity-dependent synaptic plasticity. Dysregulation of mGluR1/5 signaling is implicated in some disorders of neurodevelopment, including fragile X syndrome, the most common inherited form of intellectual disabilities and leading cause of autism. Site(s) in the intracellular loops of mGluR1/5 directly bind caveolin-1, an adaptor protein that associates with membrane rafts. Caveolin-1 is the main coat component of caveolae and organizes macromolecular signaling complexes with effector proteins and membrane receptors. We report that long-term depression (LTD) elicited by a single application of the group I mGluR selective agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) was markedly attenuated at Schaffer collateral-CA1 synapses of mice lacking caveolin-1 (Cav1 −/− ), as assessed by field recording. In contrast, multiple applications of DHPG produced LTD comparable to that in WT mice. Passive membrane properties, basal glutamatergic transmission and NMDA receptor (NMDAR)-dependent LTD were unaltered. The remaining LTD was reduced by anisomycin, an inhibitor of protein synthesis, by U0126, an inhibitor of MEK1/2 kinases, and by rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), suggesting mediation by the same mechanisms as in WT. mGluR1/5-dependent activation (phosphorylation) of MEK and extracellular signal-regulated kinase (ERK1/2) was altered in Cav1 −/− mice; basal phosphorylation was increased, but a single application of DHPG had no further effect, and after DHPG, phosphorylation was similar in WT and Cav1 −/− mice. Taken together, our findings suggest that caveolin-1 is required for normal coupling of mGluR1/5 to downstream signaling cascades and induction of mGluR-LTD.G roup I metabotropic glutamate receptors (mGluRs), mGluR1 and mGluR5, are G protein-coupled receptors enriched at excitatory synapses throughout the brain, where they regulate neuronal excitation (1, 2). mGluR1/5s play an important role in the establishment of synaptic circuitry during brain development (3, 4) and in activity-dependent forms of synaptic plasticity, including long-term potentiation and long-term depression as occur in associative learning (5-8). Dysregulated mGluR1/5 signaling is implicated in neurological, psychiatric, and cognitive disorders (8), including fragile X syndrome, the most common inherited cause of intellectual disabilities (9, 10). The broad spectrum of physiological and pathological functions in which mGluRs participate is related to their capacity to initiate diverse signaling events by G protein-dependent and -independent mechanisms (11,12).Membrane rafts (13, 14) and caveolae (15) are specialized membrane domains of the plasma membrane, enriched in cholesterol and glycosphingolipids, that serve as platforms to compartmentalize specific signaling activities at the cell surface. Caveolin-1 is an adaptor protein that interacts with an array of receptors, including m...

Neuron-targeted Caveolin-1 Protein Enhances Signaling and Promotes Arborization of Primary Neurons

“…These results extend those that have shown that the loss of Cav-1, either through siRNA or transgenic models, can blunt neuroprotection (9) and metabotropic glutamate receptor-mediated long-term depression (43,59) and accelerate a neurodegenerative phenotype (32,60,61). Our findings obtained with siRNA-mediated Cav-1 knockdown extend the role of Cav-1 in neuronal signaling to a variety of receptors in addition to glutamate.…”

“…Cav-1 and membrane/lipid rafts can regulate estrogen receptor signaling (58), glutamate receptor neurotransmission (9,43,59), and neurotrophin receptor signaling (TrkB and p75) (14,57). Although NMDAR subtypes are critical for neuroprotection against ischemic injury and for neurotransmission, their localization to extrasynaptic regions can facilitate neuronal cell death (33).…”

“…Such features include altered glutamate receptor signaling (9,43,59), motor and behavioral abnormalities, increased ischemic cerebral injury, and impaired spatial memory and cholinergic function (60 -62). Other recent evidence has demonstrated that the localization of synaptic signaling components in neuronal membrane/lipid rafts and synaptosomes is reduced in brains from aged WT and young Cav-1 KO mice and that Cav-1 KO mice develop a neuropathological phenotype similar to that of Alzheimer's disease (32).…”

Dysregulation of synaptic plasticity precedes appearance of morphological defects in a Pten conditional knockout mouse model of autism

“…Acute hippocampal slices (400 μm) were prepared from age-matched WT and mutant mice by using conventional techniques (30). fEPSPs were evoked by square pulses (10-100 μA, 100 μs) with a concentric bipolar tungsten stimulating electrode.…”

“…We next examined mGluR-LTD at DGC synapses of Pten cKO mice. mGluR-LTD is an NMDA receptor (NMDAR)-independent, protein synthesis-dependent (28) form of homosynaptic LTD and can be elicited by application of the group mGluR agonist (R,S)-3,5-dihydroxyphenylglycine (DHPG) at CA1 (29,30) and DGC synapses (31). mGluR-LTD was significantly impaired in young, middle-aged, and old Pten cKO relative to that of age-matched WT mice (Fig.…”