TY - JOUR
T1 - Impaired NMDA receptor transmission alters striatal synapses and DISC1 protein in an age-dependent manner
AU - Ramsey, Amy J.
AU - Milenkovic, Marija
AU - Oliveira, Ana F.
AU - Escobedo-Lozoya, Yasmin
AU - Seshadri, Saurav
AU - Salahpour, Ali
AU - Sawa, Akira
AU - Yasuda, Ryohei
AU - Caron, Marc G.
PY - 2011/4/5
Y1 - 2011/4/5
N2 - NMDA receptors are key regulators of synaptic plasticity, and their hypofunction is thought to contribute to the pathophysiology of CNS disorders. Furthermore, NMDA receptors participate in the formation, maintenance, and elimination of synapses. The consequences of NMDA receptor hypofunction on synapse biology were explored in a genetic mouse model, in which the levels of NMDA receptors are reduced to 10% of normal levels (i.e., NR1-knockdown mice). In these mice, synapse number is reduced in an agedependent manner; reductions are observed at the postpubertal age of 6 wk, but normal at 2 wk of age. Efforts to uncover the biochemical underpinnings of this phenomenon reveal synapsespecific reductions in 14-3-3ε protein and in Disrupted in Schizophrenia- 1 (DISC1), two schizophrenia susceptibility factors that have been implicated in the regulation of spine density. Subchronic administration of MK-801, an NMDA receptor antagonist, produces similar synaptic reductions in both spine density and DISC1, indicating that synaptic levels of DISC1 are regulated by NMDA receptor function. The synaptic reduction of DISC1 and 14-3-3ε is developmentally correlated with the age-dependent decrease in striatal spine density.
AB - NMDA receptors are key regulators of synaptic plasticity, and their hypofunction is thought to contribute to the pathophysiology of CNS disorders. Furthermore, NMDA receptors participate in the formation, maintenance, and elimination of synapses. The consequences of NMDA receptor hypofunction on synapse biology were explored in a genetic mouse model, in which the levels of NMDA receptors are reduced to 10% of normal levels (i.e., NR1-knockdown mice). In these mice, synapse number is reduced in an agedependent manner; reductions are observed at the postpubertal age of 6 wk, but normal at 2 wk of age. Efforts to uncover the biochemical underpinnings of this phenomenon reveal synapsespecific reductions in 14-3-3ε protein and in Disrupted in Schizophrenia- 1 (DISC1), two schizophrenia susceptibility factors that have been implicated in the regulation of spine density. Subchronic administration of MK-801, an NMDA receptor antagonist, produces similar synaptic reductions in both spine density and DISC1, indicating that synaptic levels of DISC1 are regulated by NMDA receptor function. The synaptic reduction of DISC1 and 14-3-3ε is developmentally correlated with the age-dependent decrease in striatal spine density.
KW - Glutamate
KW - Neurodevelopmental
UR - http://www.scopus.com/inward/record.url?scp=79955021468&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79955021468&partnerID=8YFLogxK
U2 - 10.1073/pnas.1012621108
DO - 10.1073/pnas.1012621108
M3 - Article
C2 - 21436042
AN - SCOPUS:79955021468
SN - 0027-8424
VL - 108
SP - 5795
EP - 5800
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 14
ER -