6-methyl-2-(phenylethynyl)pyridine and Learning-Disabilities

Loss of the RNA-binding fragile X protein [fragile X mental retardation protein (FMRP)] results in a spectrum of cognitive deficits, the fragile X syndrome (FXS), while aging individuals with decreased protein levels present with a subset of these symptoms and tremor. The broad range of behavioral deficits likely reflects the ubiquitous distribution and multiple functions of the protein. FMRP loss is expected to affect multiple neuronal proteins and intracellular signaling pathways, whose identity and interactions are essential in understanding and ameliorating FXS symptoms. We used heterozygous mutants and targeted RNA interference-mediated abrogation in Drosophila to uncover molecular pathways affected by FMRP reduction. We present evidence that FMRP loss results in excess metabotropic glutamate receptor (mGluR) activity, attributable at least in part to elevation of the protein in affected neurons. Using high-resolution behavioral, genetic, and biochemical analyses, we present evidence that excess mGluR upon FMRP attenuation is linked to the cAMP decrement reported in patients and models, and underlies olfactory associative learning and memory deficits. Furthermore, our data indicate positive transcriptional regulation of the fly fmr1 gene by cAMP, via protein kinase A, likely through the transcription factor CREB. Because the human Fmr1 gene also contains CREB binding sites, the interaction of mGluR excess and cAMP signaling defects we present suggests novel combinatorial pharmaceutical approaches to symptom amelioration upon FMRP attenuation.

Topics: Analysis of Variance; Animals; Animals, Genetically Modified; Avoidance Learning; Behavior, Animal; Conditioning, Classical; CREB-Binding Protein; Cyclic AMP; Drosophila; Excitatory Amino Acid Antagonists; Fragile X Mental Retardation Protein; Gene Expression Regulation; Humans; Learning Disabilities; Memory Disorders; Mushroom Bodies; Mutation; Phosphodiesterase 4 Inhibitors; Pyridines; Qa-SNARE Proteins; Receptors, Metabotropic Glutamate; RNA Interference; RNA, Messenger; Rolipram; Signal Transduction

LY 367385 (mGluR1) and MPEP (mGluR5), which are group I metabotropic glutamate receptor (mGluR) antagonists, were used to investigate their effects on pentylenetetrazole (PTZ) seizures, kindling, and kindling-related learning deficits. Both substances showed anticonvulsant efficacy against seizures induced by lower doses of PTZ (40 mg/kg), but they were ineffective in counteracting seizures evoked by higher PTZ doses. When these substances were given in the course of kindling induction, LY significantly depressed the progression of kindled seizure severity. In contrast, MPEP was ineffective in this experiment. Treatment with either LY or MPEP did not modify the reaction to challenge dose of PTZ. Kindling results in a worsening of shuttle-box learning. LY improved shuttle-box learning when administered in the course of kindling development or when given prior to the learning experiment. This suggests protective and restorative effectiveness. In contrast, MPEP was only effective on the learning performance of kindled rats when given prior to the shuttle-box experiment, which demonstrates restorative effectiveness. Kindling is associated with an increase in glutamate binding. LY counteracted this increase whereas MPEP was ineffective. It was concluded that mGluR1 and mGluR5 play a specific role in the convulsive component of kindling. The beneficial action of the antagonists on kindling-induced impairments in shuttle-box learning may be associated with their effect on glutamatergic synaptic activity.

Topics: Animals; Avoidance Learning; Behavior, Animal; Benzoates; Binding Sites; Dose-Response Relationship, Drug; Drug Administration Schedule; Epilepsies, Myoclonic; Glycine; Injections, Intraperitoneal; Injections, Intraventricular; Kindling, Neurologic; Learning Disabilities; Male; Pentylenetetrazole; Pyridines; Rats; Rats, Wistar; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Time Factors