Salient stimuli that modify behavior induce transcription of Activity regulated cytoskeleton-associated protein (Arc/Arg3.1) and transport Arc mRNA into dendrites, suggesting that local Arc translation mediates synaptic plasticity encoding such stimuli. Here we demonstrate that long-term synaptic depression (LTD) in hippocampal neurons induced by group 1 metabotropic glutamate receptors (mGluRs) relies on rapid translation of Arc. MGluR-LTD induction causes long-term increases in AMPA receptor endocytosis rate and dendritic synthesis of Arc, a component of AMPAR endocytosis machinery. Knockdown of Arc prevents mGluRs from triggering AMPAR endocytosis or LTD, and acute blockade of new Arc synthesis with antisense oligonucleotides blocks mGluR-LTD and AMPAR trafficking. In contrast, LTD induced by NMDA receptors does not persistently alter AMPAR endocytosis rate, induce Arc synthesis, or require Arc protein. These data demonstrate a role for local Arc synthesis specifically in mGluR-LTD and suggest that mGluR-LTD may be one consequence of Arc mRNA induction during experience.

Synaptically activated, rapid and dendritic synthesis of new proteins has long been proposed to mediate long-lasting changes at the synapse [1]. Studies of group 1 metabotropic glutamate receptordependent long-term depression (mGluR-LTD) have provided new insight into dendritic or local translation and plasticity. Here we highlight these exciting results and discuss how synaptic activity controls local translation, the proteins that are synthesized in dendrites, how they affect synaptic function and how altered local translational control contributes to a form of human mental retardation, Fragile X Syndrome. Rapid postsynaptic translation is required for mGluR-dependent LTDPrincipal neurons possess on average 10,000 excitatory synapses. Plasticity of individual or localized regions of synapses is necessary for the information storage capacity of the brain. Upon the discovery of polyribosomes within dendritic shafts and spines, it was suggested that rapid dendritic protein synthesis, triggered by synaptic activity, may serve as a mechanism for long-term plasticity at specific synapses. Empirical data support the role of dendritic protein synthesis in the maintenance of long-term potentiation (LTP) and depression (LTD) [2,3]. Recent advances in our understanding of localized protein synthesis in synaptic plasticity stem from studies of a form of LTD induced by activation of the Gq coupled metabotropic glutamate receptors (mGluR1 and 5; mGluR-LTD). At excitatory synapses onto CA1 pyramidal neurons, LTD can be induced pharmacologically with the group 1 mGluR agonist, DHPG, or by synaptic stimulation of mGluRs via paired-pulse low frequency stimulation of Schaffer collaterals [4, 5]. MGluR-LTD is induced in mature neurons with either paradigm where it requires rapid protein synthesis (~15 minutes) from preexisting mRNA [4,6]. In CA1, mGluR-LTD can be elicited in transected dendrites and affects only active synapses, suggesting that newly required proteins are synthesized in the dendrite and locally weaken synapses [4]. More recently, it was demonstrated that activation of Gq-coupled M1 muscarinic acetylcholine receptors (mAChRs) elicits a protein synthesis dependent LTD that occludes mGluR-LTD in CA1 [7,8]. Therefore, activation of multiple Gq coupled receptors converges upon a single common LTD mechanism that utilizes rapid, postsynaptic protein synthesis. In contrast, another well characterized form

BACKGROUND The Activity-regulated cytoskeleton-associated protein, Arc, is an immediate-early gene product implicated in various forms of synaptic plasticity. Arc promotes endocytosis of AMPA type glutamate receptors and regulates cytoskeletal assembly in neuronal dendrites. Its role in endocytosis may be mediated by its reported interaction with dynamin 2 (Dyn2), a 100 kDa GTPase that polymerizes around the necks of budding vesicles and catalyzes membrane scission. METHODS Enzymatic and turbidity assays are used in this study to monitor effects of Arc on dynamin activity and polymerization. Arc oligomerization is measured using a combination of approaches, including size exclusion chromatography, sedimentation analysis, dynamic light scattering, fluorescence correlation spectroscopy, and electron microscopy. RESULTS We present evidence that bacterially-expressed His6-Arc facilitates the polymerization of Dyn2 and stimulates its GTPase activity under physiologic conditions (37°C and 100 mM NaCl). At lower ionic strength Arc also stabilizes pre-formed Dyn2 polymers against GTP-dependent disassembly, thereby prolonging assembly-dependent GTP hydrolysis catalyzed by Dyn2. Arc also increases the GTPase activity of Dyn3, an isoform of implicated in dendrite remodeling, but does not affect the activity of Dyn1, a neuron-specific isoform involved in synaptic vesicle recycling. We further show in this study that Arc (either His6-tagged or untagged) has a tendency to form large soluble oligomers, which may function as a scaffold for dynamin assembly and activation. CONCLUSIONS and GENERAL SIGNIFICANCE The ability of Arc to enhance dynamin polymerization and GTPase activation may provide a mechanism to explain Arc-mediated endocytosis of AMPA receptors and the accompanying effects on synaptic plasticity. This study represents the first detailed characterization of the physical properties of Arc.

IMPORTANCE Genetic and environmental factors are thought to contribute to cluster headache, and cluster headache can affect multiple members of a family. A thorough understanding of its inheritance is critical to understanding the pathogenesis of this debilitating disease.OBJECTIVE To systematically review family history rates and inheritance patterns of cluster headache.EVIDENCE REVIEW A systematic review was performed in PubMed, Embase, and Cochrane Library. Search criteria were created by a librarian. Articles published between 1985 and 2016, after the publication date of a large review in 1985, were analyzed independently by 2 neurologists to identify family history rates and pedigrees. Pedigrees were analyzed by a genetic counselor. FINDINGS A total of 1995 studies were found (1988 through the search criteria and 7 through other means). Forty articles met inclusion criteria: 22 large cohort studies, 1 twin-based study, and 17 case reports or small case series. Across the 22 large cohort studies, the positive family history rate of cluster headache varied between 0% and 22%, with a median of 8.2%. The largest 5 studies, of 1134, 785, 693, 609, and 500 probands each, had a positive family history in 18.0% (numerator not provided), 5.1% (40 of 785 cases), 10.0% (numerator not provided), 2.0% (12 of 609 cases), and 11.2% (56 of 500 cases), respectively. No meta-analysis was performed, given differences in methodologies. Separately, 1 twin-based study examined 37 twin pairs and reported a concordance rate of 5.4% (2 pairs). Finally, 67 pedigrees were identified. Most pedigrees (46 of 67 [69%]) were consistent with an autosomal dominant pattern, but 19 of 67 (28%) were consistent with an autosomal recessive inheritance pattern; 10 pedigrees of probable or atypical cluster headache were identified, and all were consistent with an autosomal dominant inheritance pattern. The sex ratio for cluster headache in identified pedigrees was 1.39 (103:74) in affected men and boys compared with affected women and girls, which is lower than that of the general cluster headache population. CONCLUSIONS AND RELEVANCECluster headache is an inherited disorder in a subset of families and is associated with multiple hereditary patterns. There is an unexpectedly high preponderance of women and girls with familial cluster headache; genetic subanalyses limited to female participants are necessary to further explore this observation, because these data are otherwise masked by the higher numbers of male participants with cluster headache. Overall, this systematic review supports the notion that familial cluster headache is likely the result of multiple susceptibility genes as well as environmental factors.

IntroductionMany patients suffering from migraine gain little relief from existing treatments partly because many existing acute and preventive therapies used in migraine have been adopted from other neurologic conditions such as depression or epilepsy. Here, we present data supporting a new migraine‐specific target, the mGlu5 receptor.MethodsWe studied the effect of mGlu5 blockade using ADX10059, on neuronal firing in the trigeminocervical complex (TCC) and durovascular effects of nociceptive trigeminovascular activation in the anesthetized rat. The clinical potential of the mGlu5 mechanism was tested with ADX10059 orally in a double‐blind placebo‐controlled, parallel group, clinical trial.ResultsThe negative allosteric mGlu5 modulator ADX10059 attenuated dural vasodilator responses to meningeal stimulation in a dose‐dependent manner, comparable to naratriptan, while the N‐methyl‐d‐aspartate receptor blocker MK‐801 had no effect. ADX10059 reduced responses of trigeminocervical neurons to dural stimulation, most strikingly affecting their spontaneous firing rate. Immunostaining identified mGlu5 and not mGlu1a receptors in the TCC. The primary efficacy endpoint for the clinical trial, 2 h pain free, demonstrated a significant effect of ADX10059 375 mg, 17%, versus placebo, 5%. No serious adverse events were reported at the primary dose, with transient dizziness being the most common treatment‐emergent event at 48%.InterpretationOur findings provide preclinical and clinical proof of concept establishing mGlu5 as a novel therapeutic target in the treatment of migraine. Although ADX10059 is unsuitable as a therapeutic candidate, because of hepatoxicity detected in a subsequent study, the data open a new direction for migraine research and therapy.