Cortical synaptic NMDA receptor deficits in α7 nicotinic acetylcholine receptor gene deletion models: Implications for neuropsychiatric diseases

NEUROBIOLOGY OF DISEASE

卷:63

Article

Lin, Hong^1,2  Hsu, Fu-Chun^1,2  Baumann, Bailey H.^1,2  Coulter, Douglas A.^1,2,3  Lynch, David R.^1,2,3 

[1] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA

[2] Childrens Hosp Philadelphia, Dept Neurol, Philadelphia, PA 19104 USA

[3] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA

关键词: alpha 7 nicotinic acetylcholine receptor;    Synaptic NMDA receptor;    Extrasynaptic NMDA receptor;    D-serine;    Serine racemase;    Cortex;    Glutamatergic synaptic deficits;    Neuropsychiatric diseases;    Schizophrenia;   

DOI  :  10.1016/j.nbd.2013.11.021

来源: Elsevier

【 摘 要 】

Microdeletion of the human CHRNA7 gene (alpha 7 nicotinic acetylcholine receptor, nAChR) as well as dysfunction in N-methyl-o-aspartate receptors (NMDARs) have been associated with cortical dysfunction in a broad spectrum of neurodevelopmental and neuropsychiatric disorders including schizophrenia. However, the pathophysiological roles of synaptic vs. extrasynaptic NMDARs and their interactions with alpha 7 nAChRs in cortical dysfunction remain largely uncharacterized. Using a combination of in vivo and in vitro models, we demonstrate that alpha 7 nAChR gene deletion leads to specific loss of synaptic NMDARs and their coagonist, D-serine, as well as gluta-matergic synaptic deficits in mouse cortex. alpha 7 nAChR null mice had decreased cortical NMDAR expression and glutamatergic synapse formation during postnatal development. Similar reductions in NMDAR expression and glutamatergic synapse formation were revealed in cortical cultures lacking alpha 7 nAChRs. Interestingly, synaptic, but not extrasynaptic, NMDAR currents were specifically diminished in cultured cortical pyramidal neurons as well as in acute prefrontal cortical slices of alpha 7 nAChR null mice. Moreover, D-serine responsive synaptic NMDAR-mediated currents and levels of the D-serine synthetic enzyme serine racemase were both reduced in alpha 7 nAChR null cortical pyramidal neurons. Our findings thus identify specific loss of synaptic NMDARs and their coagonist, D-serine, as well as glutamatergic synaptic deficits in alpha 7 nAChR gene deletion models of cortical dysfunction, thereby implicating alpha 7 nAChR-mediated control of synaptic NMDARs and serine racemase/D-serine pathways in cortical dysfunction underlying many neuropsychiatric and neurodevelopmental disorders, particularly those associated with deletion of human CHRNA7. (C) 2013 Elsevier Inc. All rights reserved.

【 授权许可】

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