Protective role for type-1 metabotropic glutamate receptors against spike and wave discharges in the WAG/Rij rat model of absence epilepsy

Ngomba, Richard Teke; Santolini, Ines; Biagioni, Francesca; Molinaro, Gemma; Simonyi, Ágnes; Rijn, Clementina M. van; D'Amore, V.; Mastroiacovo, Federica; Olivieri, G.; Gradini, Roberto; Ferraguti, Francesco; Battaglia, Giuseppe; Bruno, Valeria; Puliti, Aldamaria; Luijtelaar, Gilles van; Nicoletti, Ferdinando

doi:10.1016/j.neuropharm.2011.01.007

Cited by 37 publications

(49 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, clear differences were found in the thalamus. 61 A different pattern emerged in the cortex for the mGlu2/3 receptors: six-month-old WAG/Rij rats showed an increased expression of mGlu2/3 receptors in the ventrolateral regions of the somatosensory cortex, as assessed by immunohistochemistry and Western blotting in comparison with presymptomatic WAG/Rij and age matched controls. 60 The expression of a representative of another subclass of mGlu receptors, mGlu4 was not differently expressed at the somatosensory cortex.…”

Section: Changes In Membrane Properties Of Neurons In the Neocorticalmentioning

confidence: 98%

On the Origin and Suddenness of Absences in Genetic Absence Models

2011

View full text Add to dashboard Cite

The origin of spike-wave discharges (SWDs), typical for absences, has been debated for at least half a century. While most classical views adhere to a thalamic oscillatory machinery and an active role of the cortex in modifying normal oscillations into pathological SWDs, recent studies in genetic models such as WAG/Rij and GAERS rats have challenged this proposal. It seems now well established that SWDs originate from the deep layers of the somatosensory cortex, that the activity quickly spreads over the cortex and invades the thalamus. The reticular thalamic nucleus and other thalamic nuclei provide a resonance circuitry for the amplification, spreading and entrainment of the SWDs. Conclusive evidence has been found that the changed functionality of HCN1 channels is a causative factor for the changes in local excitability and age-dependent increase in SWD. Furthermore, upregulation of two subtypes of Na+ channels, reduction of GABAB and mGlu 2/3 receptors might also play a role in the local increased excitability in WAG/Rij rats. Signal analytical studies have also challenged the view that SWDs occur suddenly from a normal background EEG. SWDs are recruited cortical responses and they develop from increasing associations within and between cortical layers and subsequently subcortical regions, triggered by the simultaneous occurrence of theta and delta precursor activity in the cortex and thalamus in case both structures are in a favorable condition, and increased directional coupling between cortex and thalamus. It is hypothesized that the cortex is the driving force throughout the whole SWD and is also responsible for its end.

show abstract

Section: Changes In Membrane Properties Of Neurons In the Neocorticalmentioning

confidence: 98%

On the Origin and Suddenness of Absences in Genetic Absence Models

2011

View full text Add to dashboard Cite

show abstract

“…We used the selective mGlu1 receptor PAM, Ro0711401, which has nanomolar affinity for mGlu1 receptors, that is systemically active, and shows an elimination half-life < 2 hours [45]. Systemic injection of Ro0711401 was shown to reduce the frequency of spike-and-wave discharges in a rat model of absence epilepsy [46], and to improve motor signs in EAE mice [39]. Of note, treatment with Ro0711401 had no effect on motor behavior in control mice or in presymptomatic SCA1 mice and did not cause gross anatomical or behavioral abnormalities besides the improvement of motor performance in symptomatic SCA1 mice.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological enhancement of mGlu1 metabotropic glutamate receptors causes a prolonged symptomatic benefit in a mouse model of spinocerebellar ataxia type 1

et al. 2013

View full text Add to dashboard Cite

BackgroundSpinocerebellar ataxia type 1 (SCA1) is a genetic disorder characterized by severe ataxia associated with progressive loss of cerebellar Purkinje cells. The mGlu1 metabotropic glutamate receptor plays a key role in mechanisms of activity-dependent synaptic plasticity in the cerebellum, and its dysfunction is linked to the pathophysiology of motor symptoms associated with SCA1. We used SCA1 heterozygous transgenic mice (Q154/Q2) as a model for testing the hypothesis that drugs that enhance mGlu1 receptor function may be good candidates for the medical treatment of SCA1.ResultsSymptomatic 30-week old SCA1 mice showed reduced mGlu1 receptor mRNA and protein levels in the cerebellum. Interestingly, these mice also showed an intense expression of mGlu5 receptors in cerebellar Purkinje cells, which normally lack these receptors. Systemic treatment of SCA1 mice with the mGlu1 receptor positive allosteric modulator (PAM), Ro0711401 (10 mg/kg, s.c.), caused a prolonged improvement of motor performance on the rotarod and the paw-print tests. A single injection of Ro0711401 improved motor symptoms for several days, and no tolerance developed to the drug. In contrast, the mGlu5 receptor PAM, VU0360172 (10 mg/kg, s.c.), caused only a short-lasting improvement of motor symptoms, whereas the mGlu1 receptor antagonist, JNJ16259685 (2.5 mg/kg, i.p.), further impaired motor performance in SCA1 mice. The prolonged symptomatic benefit caused by Ro0711401 outlasted the time of drug clearance from the cerebellum, and was associated with neuroadaptive changes in the cerebellum, such as a striking reduction of the ectopically expressed mGlu5 receptors in Purkinje cells, increases in levels of total and Ser880-phosphorylated GluA2 subunit of AMPA receptors, and changes in the length of spines in the distal dendrites of Purkinje cells.ConclusionsThese data demonstrate that pharmacological enhancement of mGlu1 receptors causes a robust and sustained motor improvement in SCA1 mice, and lay the groundwork for the development of mGlu1 receptor PAMs as novel “cerebellum-specific”, effective, and safe symptomatic drugs for the treatment of SCA1 in humans.

show abstract

“…The number of responses in the previously active hole was used as a measure of methamphetamine seeking or craving. For experiments that evaluated the effect of the systemically active mGlu1 PAM SYN119 (33) on cue-induced methamphetamine seeking, rats received an injection of vehicle or SYN119 [10 mg/kg, intraperitoneal (i.p.)] 20 min before placement in the operant chamber.…”

Section: Methodsmentioning

confidence: 99%

AMPA Receptor Plasticity in Accumbens Core Contributes to Incubation of Methamphetamine Craving

Scheyer¹,

Loweth²,

Christian³

et al. 2016

Biological Psychiatry

108

View full text Add to dashboard Cite

BACKGROUND The incubation of cue-induced drug craving in rodents provides a model of persistent vulnerability to craving and relapse in human addicts. After prolonged withdrawal, incubated cocaine craving depends on strengthening of nucleus accumbens (NAc) core synapses through incorporation of Ca2+-permeable AMPA receptors (CP-AMPARs). Through mGlu1-mediated synaptic depression, mGlu1 positive allosteric modulators (PAMs) remove CP-AMPARs from these synapses and thereby reduce cocaine craving. This study aimed to determine if similar plasticity accompanies incubation of methamphetamine craving. METHODS Rats self-administered saline or methamphetamine under extended-access conditions. Cue-induced seeking tests demonstrated incubation of methamphetamine craving. After withdrawal periods ranging from 1 to >40 days, rats underwent one of the following procedures: 1) whole-cell patch clamp recordings to characterize AMPAR transmission, 2) intra-NAc core injection of the CP-AMPAR antagonist 1-napthyl acetyl spermine (naspm) prior to a seeking test, or 3) systemic administration of an mGlu1 PAM prior to a seeking test. RESULTS Incubation of methamphetamine craving was associated with CP-AMPAR accumulation in NAc core, and both effects were maximal after ~1 week of withdrawal. Expression of incubated craving was decreased by intra-NAc naspm injection or systemic mGlu1 PAM administration. CONCLUSIONS These results are the first to demonstrate a role for the NAc in the incubation of methamphetamine craving and describe adaptations in synaptic transmission associated with this model. They establish that incubation of craving and associated CP-AMPAR plasticity occur much more rapidly during withdrawal from methamphetamine than cocaine. However, a common mGlu1-based therapeutic strategy may be helpful for recovering cocaine and methamphetamine addicts.

show abstract

Protective role for type-1 metabotropic glutamate receptors against spike and wave discharges in the WAG/Rij rat model of absence epilepsy

Cited by 37 publications

References 60 publications

On the Origin and Suddenness of Absences in Genetic Absence Models

On the Origin and Suddenness of Absences in Genetic Absence Models

Pharmacological enhancement of mGlu1 metabotropic glutamate receptors causes a prolonged symptomatic benefit in a mouse model of spinocerebellar ataxia type 1

AMPA Receptor Plasticity in Accumbens Core Contributes to Incubation of Methamphetamine Craving

Contact Info

Product

Resources

About