vu-0155041 and Disease-Models--Animal

Fragile X syndrome (FXS), the most common inherited intellectual disability, is caused by the loss of expression of the Fragile X Messenger Ribonucleoprotein (FMRP). FMRP is an RNA-binding protein that negatively regulates the expression of many postsynaptic as well as presynaptic proteins involved in action potential properties, calcium homeostasis and neurotransmitter release. FXS patients and mice lacking FMRP suffer from multiple behavioral alterations, including deficits in motor learning for which there is currently no specific treatment.. We performed electron microscopy, whole-cell patch-clamp electrophysiology and behavioral experiments to characterise the synaptic mechanisms underlying the motor learning deficits observed in Fmr1KO mice and the therapeutic potential of positive allosteric modulator of mGluR4.. We found that enhanced synaptic vesicle docking of cerebellar parallel fiber to Purkinje cell Fmr1KO synapses was associated with enhanced asynchronous release, which not only prevents further potentiation, but it also compromises presynaptic parallel fiber long-term potentiation (PF-LTP) mediated by β adrenergic receptors. A reduction in extracellular Ca. We cannot rule out that the activation of mGluR4s via systemic administration of VU0155041 can also affect other brain regions. Further studies are needed to stablish the effect of a specific activation of mGluR4 in cerebellar granule cells.. Our study shows that an increase in synaptic vesicles, SV, docking may cause the loss of PF-LTP and motor learning and social deficits of Fmr1KO mice and that the reversal of these changes by pharmacological activation of mGluR4 may offer therapeutic relief for motor learning and social deficits in FXS.

Topics: Animals; Disease Models, Animal; Fragile X Mental Retardation Protein; Fragile X Syndrome; Long-Term Potentiation; Male; Mice; Mice, Knockout; Social Behavior; Synaptic Transmission

The etiology of Autism Spectrum Disorders (ASDs) remains largely unknown. Identifying vulnerability genes for autism represents a major challenge in the field and allows the development of animal models for translational research. Mice lacking the mu opioid receptor gene (Oprm1(-/-)) were recently proposed as a monogenic mouse model of autism, based on severe deficits in social behavior and communication skills. We confirm this hypothesis by showing that adult Oprm1(-/-) animals recapitulate core and multiple comorbid behavioral symptoms of autism and also display anatomical, neurochemical, and genetic landmarks of the disease. Chronic facilitation of mGluR4 signaling, which we identified as a novel pharmacological target in ASDs in these mice, was more efficient in alleviating behavioral deficits than the reference molecule risperidone. Altogether, our data provide first evidence that disrupted mu opioid receptor signaling is sufficient to trigger a comprehensive autistic syndrome, maybe through blunted social reward processes, and this mouse model opens promising avenues for therapeutic innovation.

Topics: Aggression; Anilides; Animals; Anxiety; Behavior, Animal; Brain; Child Development Disorders, Pervasive; Convulsants; Cyclohexanecarboxylic Acids; Disease Models, Animal; Excitatory Amino Acid Agents; Female; Male; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Pentylenetetrazole; Receptors, Metabotropic Glutamate; Receptors, Opioid, mu; Seizures; Social Behavior

Group III metabotropic glutamate receptors (mGluR4,7,8) are widely distributed in the basal ganglia. Injection of group III mGluR agonists into the striatopallidal complex alleviates parkinsonian symptoms in 6-hydroxydopamine-treated rats. In vitro rodent studies have suggested that this may be partly due to modulation of synaptic transmission at striatopallidal and corticostriatal synapses through mGluR4 activation. However, the in vivo electrophysiological effects of group III mGluRs activation upon basal ganglia neurons activity in nonhuman primates remain unknown. Thus, in order to examine the anatomical substrates and physiological effects of group III mGluRs activation upon striatal and pallidal neurons in monkeys, we used electron microscopy immunohistochemistry to localize mGluR4, combined with local administration of the group III mGluR agonist L-AP4, or the mGluR4 positive allosteric modulator VU0155041, to assess the effects of group III mGluR activation on the firing rate and pattern of striatal and pallidal neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated parkinsonian monkeys. At the ultrastructural level, striatal mGluR4 immunoreactivity was localized in pre- (60%) and post-synaptic (30%) elements, while in the GPe, mGluR4 was mainly expressed pre-synaptically (90%). In the putamen, terminals expressing mGluR4 were evenly split between putative excitatory and inhibitory terminals, while in the GPe, most labeled terminals displayed the ultrastructural features of striatal-like inhibitory terminals, though putative excitatory boutons were also labeled. No significant difference was found between normal and parkinsonian monkeys. Extracellular recordings in awake MPTP-treated monkeys revealed that local microinjections of small volumes of L-AP4 resulted in increased firing rates in one half of striatal cells and one third of pallidal cells, while a significant number of neurons in both structures showed either opposite effects, or did not display any significant rate changes following L-AP4 application. VU0155041 administration had little effect on firing rates. Both compounds also had subtle effects on bursting and oscillatory properties, acting to increase the irregularity of firing. The occurrence of pauses in firing was reduced in the majority (80%) of GPe neurons after L-AP4 injection. Our findings indicate that glutamate can mediate multifarious physiological effects upon striatal and pallidal neurons through activati

Topics: Action Potentials; Aminobutyrates; Anilides; Animals; Corpus Striatum; Cyclohexanecarboxylic Acids; Disease Models, Animal; Excitatory Amino Acid Agonists; Female; Globus Pallidus; Macaca mulatta; Male; Microinjections; MPTP Poisoning; Neurons; Receptors, Metabotropic Glutamate; Synapses

Metabotropic glutamate receptors (mGluRs) are coupled to second messenger pathways via G proteins and modulate synaptic transmission. Of the eight different types of mGluRs (mGluR1-mGluR8), mGluR4, mGluR6, mGluR7, and mGluR8 are members of group III. Group III receptors are generally located presynaptically, where they regulate neurotransmitter release. Because of their role in modulating neurotransmission, mGluRs are attractive targets for therapies aimed at treating anxiety disorders. Previously we showed that the mGluR4-selective allosteric agonist VU 0155041 reduces anxiety-like behavior in wild-type male mice. Here, we explore the role of mGluR4 in adult (6-month old) and middle-aged (12-month old) male and female mice lacking this receptor. Compared to age- and sex-matched wild-type mice, middle-aged mGluR4(-/-) male mice showed increased measures of anxiety in the open field and elevated zero maze and impaired sensorimotor function on the rotarod. These changes were not seen in adult 6-month-old male mice. In contrast to the male mice, mGluR4(-/-) female mice showed reduced measures of anxiety in the open field and elevated zero maze and enhanced rotarod performance. During the hidden platform training sessions of the water maze, mGluR4(-/-) mice swam farther away from the platform than wild-type mice at 6, but not at 12, months of age. mGluR4(-/-) mice also showed enhanced amygdala-dependent cued fear conditioning. No genotype differences were seen in hippocampus-dependent contextual fear conditioning. These data indicate that effects of mGluR4 on sensorimotor function and measures of anxiety, but not cued fear conditioning, are critically modulated by sex and age.

Topics: Age Factors; Analysis of Variance; Anilides; Animals; Anxiety; Body Weight; Conditioning, Psychological; Cues; Cyclohexanecarboxylic Acids; Disease Models, Animal; Fear; Female; Gait Disorders, Neurologic; Male; Maze Learning; Memory Disorders; Mice; Mice, Knockout; Motor Activity; Receptors, Metabotropic Glutamate; Rotarod Performance Test; Sex Characteristics

Glutamate receptors (GluRs) play a critical role in pain pathway. Recent studies have shown that activation of spinal group III metabotropic GluRs attenuated hyperalgesia in neuropathic pain model rats. However, it is unclear which subtype of group III metabotropic GluRs is involved in neuropathic pain. In this study, we have shown that spinal administration of metabotropic GluRs (mGluR4)-positive allosteric modulator (VU0155041) dose dependently attenuated hyperalgesia in neuropathic pain model rats, whereas that of mGluR7-positive allosteric modulator (AMN082) did not. Furthermore, we confirmed that it was mGluR4 not mGluR7, whose expression was downregulated in the spinal dorsal horn after spinal nerve ligation. Thus, these results suggest the alteration of the spinal mGluR4 expression that contributes to the development of neuropathic pain.

Topics: Anilides; Animals; Blotting, Western; Cyclohexanecarboxylic Acids; Disease Models, Animal; Hyperalgesia; Immunohistochemistry; Male; Neuralgia; Posterior Horn Cells; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate

Metabotropic glutamate receptors (mGluRs) modulate glutamatergic and GABAergic neurotransmission. mGluR8, a member of group III receptors, is generally located presynaptically where it regulates neurotransmitter release. Previously we reported higher measures of anxiety in 6- and 12-month-old mGluR8(-/-) male mice than age- and sex-matched wild-type mice and that acute pharmacological stimulation with the mGluR8 agonist (S)-3,4,-dicarboxyphenylglycine (DCPG) or the Positive Allosteric Modulator (PAM) AZ12216052 reduced measures of anxiety in wild-type mice. As in humans and animals, ageing is associated with enhanced measures of anxiety following non-social and social challenges, increased understanding of these measures and how to potentially modulate them is particularly important in the elderly. Here we determined whether the effects of AZ12216052 on measures of anxiety are mediated by mGluR8 using 24-month-old mGluR8(-/-) and wild-type male mice. AZ12216052 also reduced measures of anxiety in the elevated zero maze and the acoustic startle response in mGluR8(-/-) mice. The remaining anxiolytic effects of AZ12216052 in mGluR8(-/-) mice might involve mGluR4, as the mGluR4 PAM VU 0155041 also reduced measures of anxiety in wild-type mice. In contrast, mGluR8(-/-) mice show enhanced social interaction but AZ12216052 does not affect social interaction in wild-type mice. Thus, while mGluR8 is an attractive target to modulate measures of anxiety and social interaction, the effects of AZ12216052 on measures of anxiety likely also involve receptors other than mGluR8.

Topics: Acetanilides; Aging; Anilides; Animals; Anxiety; Cyclohexanecarboxylic Acids; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Interpersonal Relations; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Metabotropic Glutamate; Sensory Gating; Thioglycolates

This Letter describes the synthesis and SAR of the novel positive allosteric modulator, VU0155041, a compound that has shown in vivo efficacy in rodent models of Parkinson's disease. The synthesis takes advantage of an iterative parallel synthesis approach to rapidly synthesize and evaluate a number of analogs of VU0155041.

Topics: Allosteric Regulation; Allosteric Site; Anilides; Animals; Cyclohexanecarboxylic Acids; Disease Models, Animal; Parkinson Disease; Rats; Receptors, Metabotropic Glutamate; Structure-Activity Relationship