Increased Metabotropic Glutamate Receptor 5 Signaling Underlies Obsessive-Compulsive Disorder-like Behavioral and Striatal Circuit Abnormalities in Mice

Ade, Kristen K.; Wan, Yehong; Hamann, Harold C.; O’Hare, Justin K.; Guo, Weirui; Quian, Anna; Kumar, Sunil; Bhagat, Srishti; Rodriguiz, Ramona M.; Wetsel, William C.; Conn, P. Jeffrey; Dzirasa, Kafui; Huber, Kimberly M.; Calakos, Nicole

doi:10.1016/j.biopsych.2016.04.023

Cited by 74 publications

(62 citation statements)

References 64 publications

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“…The finding that increased mGluRI activation contributes to increased anxiety-like behaviors and repeated movement execution in EAAC1 −/− mice is consistent with a key role for these neuronal glutamate transporters in the modulation of motor function and perseverative behaviors. Our data are consistent with previous work in Sapap3 knock-out mice, where increased mGluRI activation drives OCD-like behaviors via disruption of mGluR5-Homer interaction and constitutive mGluR5 signaling (Wan et al, 2011; Ade et al, 2016). Interestingly, PET studies in humans show that the mGluRI distribution volume ratio in brain regions that show functional abnormalities in OCD (e.g.…”

Section: Discussionsupporting

confidence: 93%

Neuronal glutamate transporters control dopaminergic signaling and compulsive behaviors

Bellini

Fleming

et al. 2017

Preprint

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There is an ongoing debate on the contribution of the neuronal glutamate transporter EAAC1 to the onset of compulsive behaviors. Here we use behavioral, electrophysiological, molecular and viral approaches in male and female mice to identify the molecular and cellular mechanisms by which EAAC1 controls the execution of repeated motor behaviors. Our findings show that in the striatum, a brain region implicated with movement execution, EAAC1 limits group I metabotropic glutamate receptor (mGluRI) activation, facilitates D1 dopamine receptor (D1R) expression and ensures long-term synaptic plasticity. Blocking mGluRI in slices from mice lacking EAAC1 restores D1R expression and synaptic plasticity. Conversely, activation of intracellular signaling pathways coupled to mGluRI in D1R-expressing striatal neurons of mice expressing EAAC1 leads to reduced D1R expression and increased stereotyped movement execution. These findings identify new molecular mechanisms by which EAAC1 can shape glutamatergic and dopaminergic signals and control repeated movement execution.SIGNIFICANCE STATEMENTGenetic studies implicate Slc1a1, a gene encoding the neuronal glutamate transporter EAAC1, with obsessive-compulsive disorder (OCD). EAAC1 is abundantly expressed in the striatum, a brain region that is hyperactive in OCD. What remains unknown is how EAAC1 shapes synaptic function in the striatum. Our findings show that EAAC1 limits activation of metabotropic glutamate receptors (mGluRI) in the striatum and, by doing so, it promotes D1R expression. Targeted activation of signaling cascades coupled to mGluRI in mice expressing EAAC1 reduces D1R expression and triggers repeated motor behaviors in mice. These findings provide new information on the molecular basis of OCD and suggest new avenues for its treatment.

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Section: Discussionsupporting

confidence: 93%

Neuronal glutamate transporters control dopaminergic signaling and compulsive behaviors

Bellini

Fleming

et al. 2017

Preprint

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“…Mutations in the Sapap3 gene, which encodes the synapse-associated protein 90/ postsynaptic density-95-associated protein, have been associated with TS, pathological grooming disorders, and OCD in humans (Bienvenu et al, 2009;Züchner et al, 2009;Crane et al, 2011). Sapap3-KOs demonstrate ex vivo abnormalities in striatal spiny projection neurons (SPNs), including both increased NMDAreceptor mediated and reduced AMPA-receptor mediated transmission in dorsal striatum (Welch et al, 2007;Wan et al, 2011Wan et al, , 2014Ade et al, 2016). Furthermore, consistent with human OCD literature, they also exhibit hyperactivity in central striatum at baseline and during compulsive grooming (Burguière et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Strengthened Inputs from Secondary Motor Cortex to Striatum in a Mouse Model of Compulsive Behavior

et al. 2019

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Hyperactivity in striatum is associated with compulsive behaviors in obsessive-compulsive disorder (OCD) and related illnesses, but it is unclear whether this hyperactivity is due to intrinsic striatal dysfunction or abnormalities in corticostriatal inputs. Understanding the cellular and circuit properties underlying striatal hyperactivity could help inform the optimization of targeted stimulation treatments for compulsive behavior disorders. To investigate the cellular and synaptic abnormalities that may underlie corticostriatal dysfunction relevant to OCD, we used the Sapap3 knock-out (Sapap3-KO) mouse model of compulsive behaviors, which also exhibits hyperactivity in central striatum. Ex vivo electrophysiology in double-transgenic mice was used to assess intrinsic excitability and functional synaptic input in spiny projection neurons (SPNs) and fast-spiking interneurons (FSIs) in central striatum of Sapap3-KOs and wild-type (WT) littermates. While we found no differences in intrinsic excitability of SPNs or FSIs between Sapap3-KOs and WTs, excitatory drive to FSIs was significantly increased in KOs. Contrary to predictions, lateral orbitofrontal cortex-striatal synapses were not responsible for this increased drive; optogenetic stimulation revealed that lateral orbitofrontal cortex input to SPNs was reduced in KOs (ϳ3-fold) and unchanged in FSIs. However, secondary motor area (M2) postsynaptic responses in central striatum were significantly increased (ϳ6-fold) in strength and reliability in KOs relative to WTs. These results suggest that increased M2-striatal drive may contribute to both in vivo striatal hyperactivity and compulsive behaviors, and support a potential role for presupplementary/supplementary motor cortical regions in the pathology and treatment of compulsive behavior disorders.These findings highlight an unexpected contribution of M2 projections to striatal dysfunction in the Sapap3-KO obsessivecompulsive disorder (OCD)-relevant mouse model, with M2 inputs strengthened by at least sixfold onto both spiny projection neurons and fast-spiking interneurons in central striatum. Because M2 is thought to be homologous to presupplementary/ supplementary motor areas (pre-SMA/SMA) in humans, regions important for movement preparation and behavioral sequencing, these data are consistent with a model in which increased drive from M2 leads to excessive selection of sequenced motor patterns. Together with observations of hyperactivity in pre-SMA/SMA in both OCD and Tourette syndrome, and evidence that pre-SMA is a potential target for repetitive transcranial magnetic stimulation treatment in OCD, these results support further dissection of the role of M2 in compulsivity.

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“…For instance, in hippocampus, mGlu 1 increases the frequency of spontaneous inhibitory postsynaptic currents, whereas mGlu 5 potentiates N-methyl-D-aspartate receptor currents (Mannaioni et al, 2001). In particular, mGlu 5 has been specifically implicated in a number of neuropsychiatric disorders including addiction, schizophrenia, fragile X syndrome, obsessive compulsive disorder, and Alzheimer's disease (Grueter et al, 2008;Michalon et al, 2012;Ronesi et al, 2012;Hu et al, 2014;Ade et al, 2016;Foster and Conn, 2017).…”

Section: Introductionmentioning

confidence: 99%

Activated CaMKIIαBinds to the mGlu₅Metabotropic Glutamate Receptor and Modulates Calcium Mobilization

Marks¹,

Shonesy²,

Wang³

et al. 2018

Mol Pharmacol

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Ca 21 /calmodulin-dependent protein kinase II (CaMKII) and metabotropic glutamate receptor 5 (mGlu 5 ) are critical signaling molecules in synaptic plasticity and learning/memory. Here, we demonstrate that mGlu 5 is present in CaMKIIa complexes isolated from mouse forebrain. Further in vitro characterization showed that the membrane-proximal region of the C-terminal domain (CTD) of mGlu 5a directly interacts with purified Thr286-autophosphorylated (activated) CaMKIIa. However, the binding of CaMKIIa to this CTD fragment is reduced by the addition of excess Ca 21 /calmodulin or by additional CaMKIIa autophosphorylation at non-Thr286 sites. Furthermore, in vitro binding of CaMKIIa is dependent on a tribasic residue motif Lys-Arg-Arg (KRR) at residues 866-868 of the mGlu 5a -CTD, and mutation of this motif decreases the coimmunoprecipitation of CaMKIIa with full-length mGlu 5a expressed in heterologous cells by about 50%. The KRR motif is required for two novel functional effects of coexpressing constitutively active CaMKIIa with mGlu 5a in heterologous cells. First, cell-surface biotinylation studies showed that CaMKIIa increases the surface expression of mGlu 5a . Second, using Ca 21 fluorimetry and single-cell Ca 21 imaging, we found that CaMKIIa reduces the initial peak of mGlu 5a -mediated Ca 21 mobilization by about 25% while doubling the relative duration of the Ca 21 signal. These findings provide new insights into the physical and functional coupling of these key regulators of postsynaptic signaling. [DK020593], and the Center for Stem Cell Biology. https://doi.org/10. 1124/mol.118.113142. s This article has supplemental material available at molpharm. aspetjournals.org.

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Increased Metabotropic Glutamate Receptor 5 Signaling Underlies Obsessive-Compulsive Disorder-like Behavioral and Striatal Circuit Abnormalities in Mice

Cited by 74 publications

References 64 publications

Neuronal glutamate transporters control dopaminergic signaling and compulsive behaviors

Neuronal glutamate transporters control dopaminergic signaling and compulsive behaviors

Strengthened Inputs from Secondary Motor Cortex to Striatum in a Mouse Model of Compulsive Behavior

Activated CaMKIIαBinds to the mGlu₅Metabotropic Glutamate Receptor and Modulates Calcium Mobilization

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Increased Metabotropic Glutamate Receptor 5 Signaling Underlies Obsessive-Compulsive Disorder-like Behavioral and Striatal Circuit Abnormalities in Mice

Cited by 74 publications

References 64 publications

Neuronal glutamate transporters control dopaminergic signaling and compulsive behaviors

Neuronal glutamate transporters control dopaminergic signaling and compulsive behaviors

Strengthened Inputs from Secondary Motor Cortex to Striatum in a Mouse Model of Compulsive Behavior

Activated CaMKIIαBinds to the mGlu5Metabotropic Glutamate Receptor and Modulates Calcium Mobilization

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Product

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About

Activated CaMKIIαBinds to the mGlu₅Metabotropic Glutamate Receptor and Modulates Calcium Mobilization