ABSTRACT
Aberrant glutamatergic neurotransmission may underlie the pathogenesis of schizophrenia and metabotropic glutamate receptors (mGluRs) have been implicated in the disease. We have established the localization of the group III mGluR subtype, mGluR8, in the human body and investigated the biological effects of the selective mGluR8 agonist (S)-3,4-dicarboxyphenylglycine ((S)-3,4-DCPG) in schizophrenia-related animal models. The mGlu8 receptor has a widespread CNS distribution with expression observed in key brain regions associated with schizophrenia pathogenesis including the hippocampus. (S)-3,4-DCPG inhibited synaptic transmission and increased paired-pulse facilitation in rat hippocampal slices supporting the role of mGluR8 as a presynaptic autoreceptor. Using the rat Maximal Electroshock Seizure Threshold (MEST) test, (S)-3,4-DCPG (30 mg/kg, i.p.) reduced seizure activity confirming the compound to be centrally active following systemic administration. (S)-3,4-DCPG did not reverse (locomotor) hyperactivity induced by acute administration of phenylcyclidine (PCP, 1-32 mg/kg, i.p.) or amphetamine (3-30 mg/kg, i.p.) in Sprague-Dawley rats. However, 10 nmol (i.c.v.) (S)-3.4-DCPG did reverse amphetamine-induced hyperactivity in mice although it also inhibited spontaneous locomotor activity at this dose. In addition, mGluR8 null mutant mouse behavioral phenotyping revealed an anxiety-related phenotype but no deficit in sensorimotor gating. These data provide a potential role for mGluR8 in anxiety and suggest that mGluR8 may not be a therapeutic target for schizophrenia.
Subject(s)
Brain/metabolism , Receptors, Metabotropic Glutamate/physiology , Schizophrenia/metabolism , Amphetamine/pharmacology , Animals , Anticonvulsants/pharmacology , Anxiety/genetics , Anxiety/metabolism , Autoreceptors/agonists , Autoreceptors/biosynthesis , Autoreceptors/physiology , Benzoates/pharmacology , Central Nervous System Stimulants/pharmacology , Dentate Gyrus/drug effects , Dentate Gyrus/physiology , Disease Models, Animal , Electroshock , Glycine/analogs & derivatives , Glycine/pharmacology , Humans , Male , Mice , Mice, Knockout , Motor Activity/drug effects , Phencyclidine/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Metabotropic Glutamate/agonists , Receptors, Metabotropic Glutamate/genetics , Schizophrenia/physiopathology , Seizures/etiology , Seizures/prevention & control , Synapses/physiology , Synaptic Transmission/drug effectsABSTRACT
Apolipoprotein E is the predominant brain lipoprotein and polymorphic variation in the APOE gene the major genetic susceptibly factor for late onset Alzheimer's disease (AD). Recently it was reported that carboxyl-truncated ApoE fragments induce tangle-like structures in neurons. We confirm the finding: in mouse neuroblastoma cells truncated apoE fragments lacking the carboxyterminus induce structures that have the appearance of neurofibrillary tangles. However these tangles are not induced in non-neuronal cells even in the presence of co-expressed neurofilaments or tau. Further understanding of the basis of this cell specificity might add to understanding of the cell specificity of tangles in AD.
