Pyramidal Cell Selective Ablation of N-Methyl-D-Aspartate Receptor 1 Causes Increase in Cellular and Network Excitability

被引:78
作者
Tatard-Leitman, Valerie M. [1 ,2 ]
Jutzeler, Catherine R. [1 ,2 ]
Suh, Jimmy [1 ,2 ]
Saunders, John A. [1 ,2 ]
Billingslea, Eddie N. [1 ,2 ]
Morita, Susumu [1 ]
White, Rachel [2 ]
Featherstone, Robert E. [1 ,2 ]
Ray, Rabindranath [2 ]
Ortinski, Pavel I. [2 ]
Banerjee, Anamika [2 ]
Gandal, Michael J. [1 ]
Lin, Robert [1 ]
Alexandrescu, Anamaria [1 ]
Liang, Yuling [1 ,2 ]
Gur, Raquel E. [2 ]
Borgmann-Winter, Karin E. [2 ]
Carlson, Gregory C. [2 ]
Hahn, Chang-Gyu [2 ]
Siegel, Steven J. [1 ,2 ]
机构
[1] Univ Penn, Translat Neurosci Program, Philadelphia, PA 19104 USA
[2] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA
关键词
Gamma frequency; GIRK; Hyperexcitability; NMDAR1; Pyramidal neurons; Schizophrenia; DORSOLATERAL PREFRONTAL CORTEX; AUDITORY-EVOKED POTENTIALS; RECTIFYING POTASSIUM CHANNELS; MESSENGER-RNA EXPRESSION; NMDAR1 KNOCKOUT MICE; INBRED MOUSE STRAINS; WORKING-MEMORY; GENE-EXPRESSION; GLUTAMATERGIC NEUROTRANSMISSION; SCHIZOPHRENIC-PATIENTS;
D O I
10.1016/j.biopsych.2014.06.026
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
BACKGROUND: Neuronal activity at gamma frequency is impaired in schizophrenia (SZ) and is considered critical for cognitive performance. Such impairments are thought to be due to reduced N-methyl-D-aspartate receptor (NMDAR)-mediated inhibition from parvalbumin interneurons, rather than a direct role of impaired NMDAR signaling on pyramidal neurons. However, recent studies suggest a direct role of pyramidal neurons in regulating gamma oscillations. In particular, a computational model has been proposed in which phasic currents from pyramidal cells could drive synchronized feedback inhibition from interneurons. As such, impairments in pyramidal neuron activity could lead to abnormal gamma oscillations. However, this computational model has not been tested experimentally and the molecular mechanisms underlying pyramidal neuron dysfunction in SZ remain unclear. METHODS: In the present study, we tested the hypothesis that SZ-related phenotypes could arise from reduced NMDAR signaling in pyramidal neurons using forebrain pyramidal neuron specific NMDA receptor 1 knockout mice. RESULTS: The mice displayed increased baseline gamma power, as well as sociocognitive impairments. These phenotypes were associated with increased pyramidal cell excitability due to changes in inherent membrane properties. Interestingly, mutant mice showed decreased expression of GIRK2 channels, which has been linked to increased neuronal excitability. CONCLUSIONS: Our data demonstrate for the first time that NMDAR hypofunction in pyramidal cells is sufficient to cause electrophysiological, molecular, neuropathological, and behavioral changes related to SZ.
引用
收藏
页码:556 / 568
页数:13
相关论文
共 111 条
[81]  
Moghaddam B, 1997, J NEUROSCI, V17, P2921
[82]   Mice with reduced NMDA receptor expression display behaviors related to schizophrenia [J].
Mohn, AR ;
Gainetdinov, RR ;
Caron, MG ;
Koller, BH .
CELL, 1999, 98 (04) :427-436
[83]   Alterations in somatostatin mRNA expression in the dorsolateral prefrontal cortex of subjects with schizophrenia or schizoaffective disorder [J].
Morris, Harvey M. ;
Hashimoto, Takanori ;
Lewis, David A. .
CEREBRAL CORTEX, 2008, 18 (07) :1575-1587
[84]   Ketamine Disrupts Theta Modulation of Gamma in a Computer Model of Hippocampus [J].
Neymotin, Samuel A. ;
Lazarewicz, Maciej T. ;
Sherif, Mohamed ;
Contreras, Diego ;
Finkel, Leif H. ;
Lytton, William W. .
JOURNAL OF NEUROSCIENCE, 2011, 31 (32) :11733-11743
[85]  
Padgett CL, 2010, ADV PHARMACOL, V58, P123, DOI 10.1016/S1054-3589(10)58006-2
[86]   Enrichment induces structural changes and recovery from nonspatial memory deficits in CA1 NMDAR1-knockout mice [J].
Rampon, C ;
Tang, YP ;
Goodhouse, J ;
Shimizu, E ;
Kyin, M ;
Tsien, JZ .
NATURE NEUROSCIENCE, 2000, 3 (03) :238-244
[87]   Event-related EEG time-frequency analysis: An overview of measures and an analysis of early gamma band phase locking in schizophrenia [J].
Roach, Brian J. ;
Mathalon, Daniel H. .
SCHIZOPHRENIA BULLETIN, 2008, 34 (05) :907-926
[88]   A mouse model system for genetic analysis of sociability: C57BL/6J versus BALB/cJ inbred mouse strains [J].
Sankoorikal, GMV ;
Kaercher, KA ;
Boon, CJ ;
Lee, JK ;
Brodkin, ES .
BIOLOGICAL PSYCHIATRY, 2006, 59 (05) :415-423
[89]   Loss of RBPj in Postnatal Excitatory Neurons Does Not Cause Neurodegeneration or Memory Impairments in Aged Mice [J].
Sato, Chihiro ;
Turkoz, Mustafa ;
Dearborn, Joshua T. ;
Wozniak, David F. ;
Kopan, Raphael ;
Hass, Matthew R. .
PLOS ONE, 2012, 7 (10)
[90]   Event-related theta oscillations during working memory tasks in patients with schizophrenia and healthy controls [J].
Schmiedt, C ;
Brand, A ;
Hildebrandt, H ;
Basar-Eroglu, C .
COGNITIVE BRAIN RESEARCH, 2005, 25 (03) :936-947