Agrin regulates neuronal responses to excitatory neurotransmitters in vitro and in vivo.
Agrin mediates motor neuron-induced differentiation of the postsynaptic apparatus of the neuromuscular junction but its function in brain remains unknown. Here we report that expression of c-fos, induced by activation of nicotinic or glutamatergic receptors, was significantly lower in cortical neurons cultured from agrin-deficient mutant mouse embryos compared to wildtype. Agrin-deficient neurons also exhibited increased resistance to excitotoxic injury. Treatment with recombinant agrin restored glutamate-induced c-fos expression and excitotoxicity of the agrin-deficient neurons to near wild-type levels, confirming the agrin dependence of the phenotype. The observation that c-fos induction by activation of voltage-gated Ca2+ channels is also reduced in agrin-deficient neurons raises the possibility that agrin may play a wider role by regulating responses to Ca(2+)-mediated signals. Consistent with the decline in response of cultured mutant neurons to glutamate, decreases in kainic acid-induced seizure and mortality were observed in adult agrin heterozygous mice. Together, these data demonstrate that agrin plays an important role in defining neuronal responses to excitatory neurotransmitters both in vitro and in vivo.
Hilgenberg
Lutz G W
LG
Department of Anatomy and Neurobiology, University of California at Irvine, Irvine, California 92697, USA.
Ho
Kathleen D
KD
Lee
Daewoo
D
O'Dowd
Diane K
DK
Smith
Martin A
MA
D018171:Agrin / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D015220:Calcium Channels / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology; D002450:Cell Communication / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004594:Electrophysiology; D004827:Epilepsy / Q000378:metabolism / Q000503:physiopathology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005838:Genotype; D018698:Glutamic Acid / Q000378:metabolism* / Q000494:pharmacology; D006579:Heterozygote; D006720:Homozygote; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D009498:Neurotoxins / Q000494:pharmacology; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D010641:Phenotype; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis / Q000096:biosynthesis; D017470:Receptors, Glutamate / Q000032:analysis / Q000502:physiology
D018171:Agrin; D015220:Calcium Channels; D018690:Excitatory Amino Acid Agonists; D009498:Neurotoxins; D018722:Nicotinic Agonists; D016760:Proto-Oncogene Proteins c-fos; D017470:Receptors, Glutamate; D018698:Glutamic Acid; D009538:Nicotine; D007608:Kainic Acid