TY - JOUR
T1 - Positive allosteric modulation of metabotropic glutamate 4 (mGlu4) receptors enhances spontaneous and evoked absence seizures
AU - Ngomba, R. T.
AU - Ferraguti, F.
AU - Badura, A.
AU - Citraro, R.
AU - Santolini, I.
AU - Battaglia, G.
AU - Bruno, V.
AU - De Sarro, G.
AU - Simonyi, A.
AU - van Luijtelaar, G.
AU - Nicoletti, F.
PY - 2008/2
Y1 - 2008/2
N2 - Individual metabotropic glutamate (mGlu) receptor subtypes have been implicated in the pathophysiology of epileptic seizures, and are potential targets for novel antiepileptic drugs. Here, we examined the role of the mGlu4 receptor subtype in absence seizures using as models: (i) WAG/Rij rats, which develop spontaneous absence seizures after 2-3 months of age; and (ii) mice treated with pentylentetrazole (PTZ, 30 mg/kg, s.c.). Expression of mGlu4 receptors was enhanced in the reticular thalamic nucleus (RTN) of symptomatic WAG/Rij rats as compared with age-matched controls, as assessed by immunoblotting and immunohistochemistry. No changes were found in other regions of WAG/Rij rats including ventrobasal thalamic nuclei, somatosensory cortex, and hippocampus. Electron microscopy and in situ hybridization data suggested that mGlu4 receptors in the RTN are localized on excitatory cortical afferents. Systemic injection of the selective mGlu4 receptor positive allosteric modulator, N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen1a-carboxamide (PHCCC, 10 mg/kg, s.c.), substantially enhanced the number of spike-and-wave discharges (SWDs) in WAG/Rij rats. Injection of PHCCC also enhanced absence-like seizures in PTZ-treated mice, whereas it was totally inactive in mGlu4 receptor knockout mice, which were intrinsically resistant to PTZ-induced seizures, as expected. This data supports the hypothesis that activation of mGlu4 receptors participates in the generation of absence seizures which can be exacerbated with the use of a positive allosteric modulator.
AB - Individual metabotropic glutamate (mGlu) receptor subtypes have been implicated in the pathophysiology of epileptic seizures, and are potential targets for novel antiepileptic drugs. Here, we examined the role of the mGlu4 receptor subtype in absence seizures using as models: (i) WAG/Rij rats, which develop spontaneous absence seizures after 2-3 months of age; and (ii) mice treated with pentylentetrazole (PTZ, 30 mg/kg, s.c.). Expression of mGlu4 receptors was enhanced in the reticular thalamic nucleus (RTN) of symptomatic WAG/Rij rats as compared with age-matched controls, as assessed by immunoblotting and immunohistochemistry. No changes were found in other regions of WAG/Rij rats including ventrobasal thalamic nuclei, somatosensory cortex, and hippocampus. Electron microscopy and in situ hybridization data suggested that mGlu4 receptors in the RTN are localized on excitatory cortical afferents. Systemic injection of the selective mGlu4 receptor positive allosteric modulator, N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen1a-carboxamide (PHCCC, 10 mg/kg, s.c.), substantially enhanced the number of spike-and-wave discharges (SWDs) in WAG/Rij rats. Injection of PHCCC also enhanced absence-like seizures in PTZ-treated mice, whereas it was totally inactive in mGlu4 receptor knockout mice, which were intrinsically resistant to PTZ-induced seizures, as expected. This data supports the hypothesis that activation of mGlu4 receptors participates in the generation of absence seizures which can be exacerbated with the use of a positive allosteric modulator.
KW - Absence epilepsy
KW - mGlu4 metabotropic glutamate receptors
KW - Pentylentetrazole (PTZ)
KW - Spike-wave discharges
KW - WAG/Rij rats
UR - http://www.scopus.com/inward/record.url?scp=38149108182&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=38149108182&partnerID=8YFLogxK
U2 - 10.1016/j.neuropharm.2007.10.004
DO - 10.1016/j.neuropharm.2007.10.004
M3 - Article
C2 - 18022649
AN - SCOPUS:38149108182
VL - 54
SP - 344
EP - 354
JO - Neuropharmacology
JF - Neuropharmacology
SN - 0028-3908
IS - 2
ER -