Expression analysis of metabotropic glutamate receptors I and III in mouse strains with different susceptibility to experimental temporal lobe epilepsy

ArticleinNeuroscience Letters 375(3):192-7 · March 2005with3 Reads
DOI: 10.1016/j.neulet.2004.11.008 · Source: PubMed
Increased hippocampal excitability constitutes a pathogenetic hallmark of pharmacoresistant human temporal lobe epilepsy (TLE). Metabotropic glutamate receptors (mGluRs) can be subdivided into three classes based on sequence homologies, mechanisms of signal transduction as well as pharmacological characteristics. Generally, class I mGluRs mediate neuronal excitation whereas activation of class II and III mGluRs decreases synaptic transmission. Changes in expression of class I and III mGluR subunits have been described in human TLE. It remains to be determined whether altered mGluR expression relates to differences in seizure susceptibility or hippocampal damage. Here, we examine the transcription levels of mGluRs class I (mGluR1 and 5) and III (mGluR4 and 7) in experimental TLE and correlate differential mGluR subunit expression with mouse-strain-dependent susceptibility to TLE induced by pilocarpine. Expression of mGluRs 1, 4, 5 and 7 was determined in epileptic dentate gyrus granule cells (DG) in CD1, C57BL/6 and FVB/N mice by real time RT-PCR. FVB/N mice appear significantly more vulnerable to pilocarpine-induced seizures than C57BL/6 and CD1 strains. RT-PCR analysis demonstrates an increased expression of inhibitory mGluR 4 and downregulation of excitatory mGluR 1 in epileptic CD1 mice and a decrease of the excitatory mGluRs 1 and 5 in C57BL/6 (p<0.05, n=6 each) but not in the FVB/N strain. These results correlate differential expression of excitatory class mGluR I and inhibitory class mGluR III to seizure susceptibility and hippocampal damage. Our data suggest mGluRs class I and III as interesting potential therapeutic targets to interfere with hippocampal epileptogenesis and hyperexcitability.
    • "Group III mGlu receptors can inhibit glutamate and GABA release upon activation, which influences neuronal excitability and consequently may play a role in epileptic seizures (Chapman, 2000 ). Interestingly, alterations in group III mGlu receptor expression have been shown in animal models of epilepsy (Chen et al., 2005). mGlu 4 and mGlu 8 receptor expression was shown to be changed in patients with medial temporal lobe epilepsy (Tang and Lee, 2001). "
    [Show abstract] [Hide abstract] ABSTRACT: L-glutamate is produced by a great variety of peripheral tissues in both health and disease. Like other components of the glutamatergic system, metabotropic glutamate (mGlu) receptors also have a widespread distribution outside the central nervous system (CNS). In particular, group III mGlu receptors have been recently found in human stomach and colon revealing an extraordinary potential for these receptors in the treatment of peripheral disorders, including gastrointestinal dysfunction. The significance of these findings is that pharmacological tools originally designed for mGlu receptors in the CNS may also be directed towards new disease targets in the periphery. Targeting mGlu receptors can also be beneficial in the treatment of disorders involving central components together with gastrointestinal dysfunction, such as irritable bowel syndrome, which can be co-morbid with anxiety and depression. Conversely, the development of more specific therapeutic approaches for mGlu ligands both centrally as in the gut will depend on the elucidation of tissue-specific elements in mGlu receptor signalling.
    Full-text · Article · Oct 2012
    • "Transgenic mice that lack the receptor (mGluR4 -/-) are resistant to absence-like seizures induced by low doses of the GABA-A receptor antagonist pentetrazol (PTZ) (Snead et al. 2000, Wang et al. 2005, Ngomba et al. 2008). Data supporting a role for mGluR4 in other types of epileptic seizures are controversial (Lie et al. 2000, Corti et al. 2002, Chen et al. 2005, Lavreysen and Dautzenberg 2008). The action of drugs in models of absences and other types of epileptic seizures is often opposite (GABA-B receptor antagonist – Vergnes et al. 1997, ethosuximide – Mareš 1998); therefore, we expected an anticonvulsant action of PHCCC in convulsive seizures. "
    [Show abstract] [Hide abstract] ABSTRACT: The activation of metabotropic glutamate receptors subtype 4 (mGluR4) potentiates models of absence seizures in adult rats. These seizures are age-dependent, but data concerning the role of mGluR4 in immature brain is insufficient. N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1acarboxamide (PHCCC), which is a positive allosteric modulator of these receptors, was used in three different models of seizures in immature rats: 1) convulsions induced by high doses of pentetrazol (PTZ; a model of generalised tonic-clonic seizures); 2) rhythmic electro-encephalographic (EEG) activity induced by low doses of PTZ (a model of absence seizures); and 3) electrically elicited cortical afterdischarges (ADs, a model of myoclonic seizures). We administered four doses of PHCCC (1, 3, 10 and 20 mg/kg) in PTZ-induced convulsions and two doses (3 and 10 mg/kg) in the two electrophysiological models of freely moving rats with implanted electrodes. Every dose and age group consisted of from 8 to 10 rats. PTZ-elicited convulsions were not significantly influenced by PHCCC. In contrast, PHCCC potentiated the effect of a subconvulsant dose (60 mg/kg) of PTZ. The 10-mg/kg dose of PHCCC significantly prolonged the duration of PTZ-induced rhythmic activity episodes and shortened the intervals between individual episodes in 25-day-old rats (P25). In contrast, this potentiation was not seen in P18 rats. Cortical ADs were significantly prolonged with repeated stimulations by both doses of PHCCC in P12 and P18 animals. P25 rats exhibited only slightly longer AD durations. In conclusion, we did not find any anticonvulsant effect of PHCCC. On the contrary, proconvulsant action was demonstrated in all three models in immature rats.
    Full-text · Article · Oct 2012
    • "The well-established pilocapine model for temporal lobe epilepsy was induced (Cavalheiro et al., 1996; Shibley and Smith, 2002; Chen et al., 2005). Pilocarpine (290–340 mg/kg i.p.) was injected to adult (8–16 weeks old, 26–34 g BW) male mice 15 min after pre-treatment with methyl-scopolamine (1.5 mg/kg i.p.). "
    [Show abstract] [Hide abstract] ABSTRACT: Recent studies show a key role of brain inflammation in epilepsy. However, the mechanisms controlling brain immune response are only partly understood. In the periphery, acetylcholine (ACh) release by the vagus nerve restrains inflammation by inhibiting the activation of leukocytes. Recent reports suggested a similar anti-inflammatory effect for ACh in the brain. Since brain cholinergic dysfunctions are documented in epileptic animals, we explored changes in brain cholinergic gene expression and associated immune response during pilocarpine-induced epileptogenesis. Levels of acetylcholinesterase (AChE) and inflammatory markers were measured using real-time RT-PCR, in-situ hybridization and immunostaining in wild type (WT) and transgenic mice over-expressing the "synaptic" splice variant AChE-S (TgS). One month following pilocarpine, mice were video-monitored for spontaneous seizures. To test directly the effect of ACh on the brain's innate immune response, cytokines expression levels were measured in acute brain slices treated with cholinergic agents. We report a robust up-regulation of AChE as early as 48 h following pilocarpine-induced status epilepticus (SE). AChE was expressed in hippocampal neurons, microglia, and endothelial cells but rarely in astrocytes. TgS mice overexpressing AChE showed constitutive increased microglial activation, elevated levels of pro-inflammatory cytokines 48 h after SE and accelerated epileptogenesis compared to their WT counterparts. Finally we show a direct, muscarine-receptor dependant, nicotine-receptor independent anti-inflammatory effect of ACh in brain slices maintained ex vivo. Our work demonstrates for the first time, that ACh directly suppresses brain innate immune response and that AChE up-regulation after SE is associated with enhanced immune response, facilitating the epileptogenic process. Our results highlight the cholinergic system as a potential new target for the prevention of seizures and epilepsy.
    Full-text · Article · May 2012
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