Impaired maturation of dendritic spines without disorganization of cortical cell layers in mice lacking NRG1/ErbB signaling in the central nervous system.
Neuregulin-1 (NRG1) and its ErbB2/B4 receptors are encoded by candidate susceptibility genes for schizophrenia, yet the essential functions of NRG1 signaling in the CNS are still unclear. Using CRE/LOX technology, we have inactivated ErbB2/B4-mediated NRG1 signaling specifically in the CNS. In contrast to expectations, cell layers in the cerebral cortex, hippocampus, and cerebellum develop normally in the mutant mice. Instead, loss of ErbB2/B4 impairs dendritic spine maturation and perturbs interactions of postsynaptic scaffold proteins with glutamate receptors. Conversely, increased NRG1 levels promote spine maturation. ErbB2/B4-deficient mice show increased aggression and reduced prepulse inhibition. Treatment with the antipsychotic drug clozapine reverses the behavioral and spine defects. We conclude that ErbB2/B4-mediated NRG1 signaling modulates dendritic spine maturation, and that defects at glutamatergic synapses likely contribute to the behavioral abnormalities in ErbB2/B4-deficient mice.
Barros
Claudia S
CS
Department of Cell Biology, Institute of Childhood and Neglected Disease, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Calabrese
Barbara
B
Chamero
Pablo
P
Roberts
Amanda J
AJ
Korzus
Ed
E
Lloyd
Kent
K
Stowers
Lisa
L
Mayford
Mark
M
Halpain
Shelley
S
Müller
Ulrich
U
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D002490:Central Nervous System; D002540:Cerebral Cortex / Q000166:cytology*; D003024:Clozapine / Q000494:pharmacology; D049229:Dendritic Spines / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000502:physiology*; D020890:Neuregulin-1; D018739:Oncogene Proteins v-erbB / Q000172:deficiency / Q000502:physiology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology*; D017470:Receptors, Glutamate; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; D014150:Antipsychotic Agents; D003024:Clozapine; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; D018739:Oncogene Proteins v-erbB; D018719:Erb-b2 Receptor Tyrosine Kinases; D017470:Receptors, Glutamate; C490581:Nrg1 protein, mouse