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Cellular Mechanism of Synchrony Impairments in Schizophrenia

精神分裂症同步性损伤的细胞机制

基本信息

批准号：
9918993
负责人：
Kazutoshi Nakazawa
金额：
$ 79.38万
依托单位：
SOUTHERN RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9918993
关键词：
Ablation Action Potentials Address Adult Agonist Animals Auditory area Behavior Behavioral Characteristics Cognitive Cognitive deficits Data Development Disease Down-Regulation Electrophysiology (science)Engineering Enzymes Exhibits Frequencies Functional disorder Genes Glycogen Synthase Kinase 3 Goals Hippocampus (Brain)Human Impaired cognition Impairment In Vitro Interneurons Ketamine Lead Measures Mediating Mediator of activation protein Medical Membrane Potentials Methods Mission Modeling Mus Mutant Strains Mice N-Methyl-D-Aspartate Receptors NMDA receptor A1 Neurons Parvalbumins Pathogenesis Pharmacology Phencyclidine Phenotype Physiological Play Preparation Process Protein Isoforms Pyramidal Cells Reflex action Research Role Schizophrenia Short-Term Memory Slice Spike Potential Study models Symptoms System Techniques Testing Transgenic Mice Transgenic Organisms United States National Institutes of Health Up-Regulation cognitive function functional restoration gamma-Aminobutyric Acid in vivo inhibitor/antagonist insight loss of function mutation mouse model mutant new therapeutic target novel novel therapeutics postnatal postnatal development postsynaptic neurons prepulse inhibition public health relevance relating to nervous system restoration

项目摘要

Abstract Abnormal neuronal synchrony at gamma range, often observed in schizophrenia, may be associated with cognitive deficits. Although evidence suggests that cortical fast-spiking interneurons targeting pyramidal cells may be involved in neuronal synchrony, cellular basis of abnormal neuronal synchrony in schizophrenia remains to be identified. We recently demonstrated that early postnatal deletion of NMDA receptors in cortical and hippocampal interneurons, majority of which are parvalbumin containing, was sufficient to trigger several pathophysiological features in mice that resemble human schizophrenia. The mutant mice exhibit several behavioral cognitive-like deficits and prepulse inhibition of the startle reflex. They also display a diminished spike synchrony between cortical pyramidal cells and a deficit in tone-evoked gamma frequency oscillatory activity of local field potentials in auditory cortex, measured by in vivo recordings. It is crucial to delineate the underlying mechanisms of the synchronous firing impairment of postsynaptic neurons following NMDA receptor ablation in cortical interneurons. We recently discovered that glycogen synthase kinase 3 (GSK3) is up- regulated and Cav2.1 (P/Q-type) channel currents are diminished in NMDAR-deleted fast-spiking interneurons of the mutant mice. Furthermore, inhibition of GSK3 activity augmented Cav2.1 channel currents and largely ameliorates the deficit in synchronized GABA release ex vivo. We hypothesize that that GSK3 up-regulation in the NMDA receptor-deficient fast-spiking interneurons down-regulates Cav2.1 channel function, which impairs synchronized GABA release and synchronized oscillations in the cortex producing cognitive dysfunction. The objective of this application is to determine whether dysregulation of GSK3 and Cav2.1 channels in the NMDA receptor-deleted fast-spiking neurons is crucial for an impaired synchronized GABA release and whether functional restoration of these molecules rescues not only in vivo abnormal neuronal synchrony but also behavioral cognitive dysfunction. The proposed studies may yield new insights into cellular mechanisms of cortical neuronal synchrony, potentially leading to development of novel drugs for cognitive dysfunction of schizophrenics, which is currently medically intractable.

摘要

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Spatial and temporal boundaries of NMDA receptor hypofunction leading to schizophrenia.

DOI：
10.1038/s41537-016-0003-3
发表时间：
2017
期刊：
NPJ schizophrenia
影响因子：
5.4
作者：
Nakazawa K;Jeevakumar V;Nakao K
通讯作者：
Nakao K

Neuropsychiatric Phenotypes Produced by GABA Reduction in Mouse Cortex and Hippocampus.

DOI：
10.1038/npp.2017.296
发表时间：
2018-05
期刊：
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
影响因子：
0
作者：
Kolata SM;Nakao K;Jeevakumar V;Farmer-Alroth EL;Fujita Y;Bartley AF;Jiang SZ;Rompala GR;Sorge RE;Jimenez DV;Martinowich K;Mateo Y;Hashimoto K;Dobrunz LE;Nakazawa K
通讯作者：
Nakazawa K

Electrophysiological evidence for defective fast-spiking GABAergic neurones in a schizophrenia model.

精神分裂症模型中存在缺陷的快速放电 GABA 能神经元的电生理学证据。

DOI：
10.1111/apha.12817
发表时间：
2017
期刊：
Acta physiologica (Oxford, England)
影响因子：
0
作者：
Nakazawa,K
通讯作者：
Nakazawa,K

5-HT2A receptor dysregulation in a schizophrenia relevant mouse model of NMDA receptor hypofunction.

DOI：
10.1038/s41398-022-01930-0
发表时间：
2022-04-22
期刊：
TRANSLATIONAL PSYCHIATRY
影响因子：
6.8
作者：
Nakao, Kazuhito;Singh, Mahendra;Sapkota, Kiran;Fitzgerald, Andrew;Hablitz, John J.;Nakazawa, Kazu
通讯作者：
Nakazawa, Kazu

Schizophrenia-Like Dopamine Release Abnormalities in a Mouse Model of NMDA Receptor Hypofunction.

DOI：
10.1093/schbul/sby003
发表时间：
2019-01-01
期刊：
Schizophrenia bulletin
影响因子：
6.6
作者：
Nakao K;Jeevakumar V;Jiang SZ;Fujita Y;Diaz NB;Pretell Annan CA;Eskow Jaunarajs KL;Hashimoto K;Belforte JE;Nakazawa K
通讯作者：
Nakazawa K