PubMed Health⌕ Search
Home/Archive/PubMed

PubMed · 15753239

Hippocampal complexin proteins and cognitive dysfunction in schizophrenia.

Ken Sawada·Alasdair M Barr·Masato Nakamura·Kunimasa Arima·Clint E Young·Andrew J Dwork·Peter Falkai·Anthony G Phillips·William G Honer
View original source ↗Export metadata ↓

Abstract

BACKGROUND: Converging neuroimaging and postmortem evidence indicates synaptic terminals are abnormal in schizophrenia. A putative molecular mechanism implicates abnormalities of proteins involved in the presynaptic secretory machinery, including the modulator proteins complexin I and complexin II. OBJECTIVES: To determine the amount and distribution of complexin proteins in the hippocampus of subjects with schizophrenia, in parallel with markers for excitatory and inhibitory nerve terminals. The functional implications were also investigated. DESIGN: We used immunocytochemistry to study complexin I and complexin II proteins in hippocampus, as well as the vesicular transporters for gamma-aminobutyric acid (GABA) and for glutamate. Immunocytochemical findings were correlated with cognitive function assessed through medical record review. To further explore the implications of the human findings, we studied rats exposed to haloperidol, amphetamine, and ketamine as well as rats trained in memory tasks. SUBJECTS: We studied hippocampal sections from 12 subjects with schizophrenia and 12 subjects with no known neuropsychiatric disorder. RESULTS: The absolute values and ratio of the hippocampal presynaptic proteins complexin II-complexin I were lower in subjects with schizophrenia. Disturbances in the complexin proteins in subjects with schizophrenia were greater than those observed for vesicular gamma-aminobutyric acid or vesicular glutamate transporters. The lower complexin II-complexin I ratio in several hippocampal subfields in subjects with schizophrenia was inversely correlated with the severity of antemortem cognitive impairment. In contrast, the hippocampal complexin II-complexin I ratio was higher in rats trained in a memory task compared with untrained rats. Treatment of rats with antipsychotic drugs or with the psychotomimetic drugs amphetamine or ketamine did not alter the complexin II-complexin I ratio. CONCLUSIONS: The pathology of hippocampal complexin proteins might play an important role in schizophrenia, especially concerning cognitive disturbances.

Explore related subjects

Adaptor Proteins, Vesicular TransportAgedAnimalsAntipsychotic AgentsBehavior, AnimalCognition DisordersDisease Models, AnimalFemaleHaloperidolHippocampusHumansImmunohistochemistryKetamineMaleMaze LearningMembrane Transport ProteinsMiddle AgedNerve Tissue ProteinsPresynaptic TerminalsRatsRats, Sprague-DawleySchizophreniaSchizophrenic PsychologyVesicular Glutamate Transport Protein 1Vesicular Inhibitory Amino Acid Transport ProteinsJournal ArticleResearch Support, Non-U.S. Gov't

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Ken Sawada, Alasdair M Barr, Masato Nakamura, Kunimasa Arima, Clint E Young, Andrew J Dwork, Peter Falkai, Anthony G Phillips, William G Honer. 2005. Hippocampal complexin proteins and cognitive dysfunction in schizophrenia.. https://doi.org/10.1001/archpsyc.62.3.263

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related citations

PubMed2007

Innate immune responses to endosymbiotic Wolbachia bacteria in Brugia malayi and Onchocerca volvulus are dependent on TLR2, TLR6, MyD88, and Mal, but not TLR4, TRIF, or TRAM.

The discovery that endosymbiotic Wolbachia bacteria play an important role in the pathophysiology of diseases caused by filarial nematodes, including lymphatic filariasis and onchocerciasis (river blindness) has transformed our approach to these disabling diseases. Because these parasites infect hundreds of millions of individuals worldwide, understanding host factors involved in the pathogenesis of filarial-induced diseases is paramount. However, the role of early innate responses to filarial and Wolbachia ligands in the development of filarial diseases has not been fully elucidated. To determine the role of TLRs, we used cell lines transfected with human TLRs and macrophages from TLR and adaptor molecule-deficient mice and evaluated macrophage recruitment in vivo. Extracts of Brugia malayi and Onchocerca volvulus, which contain Wolbachia, directly stimulated human embryonic kidney cells expressing TLR2, but not TLR3 or TLR4. Wolbachia containing filarial extracts stimulated cytokine production in macrophages from C57BL/6 and TLR4(-/-) mice, but not from TLR2(-/-) or TLR6(-/-) mice. Similarly, macrophages from mice deficient in adaptor molecules Toll/IL-1R domain-containing adaptor-inducing IFN-beta and Toll/IL-1R domain-containing adaptor-inducing IFN-beta-related adaptor molecule produced equivalent cytokines as wild-type cells, whereas responses were absent in macrophages from MyD88(-/-) and Toll/IL-1R domain-containing adaptor protein (TIRAP)/MyD88 adaptor-like (Mal) deficient mice. Isolated Wolbachia bacteria demonstrated similar TLR and adaptor molecule requirements. In vivo, macrophage migration to the cornea in response to filarial extracts containing Wolbachia was dependent on TLR2 but not TLR4. These results establish that the innate inflammatory pathways activated by endosymbiotic Wolbachia in B. malayi and O. volvulus filaria are dependent on TLR2-TLR6 interactions and are mediated by adaptor molecules MyD88 and TIRAP/Mal.

Adaptor Proteins, Vesicular Transport↗
PubMed2007

A new inborn error of glycosylation due to a Cog8 deficiency reveals a critical role for the Cog1-Cog8 interaction in COG complex formation.

The hetero-octameric conserved oligomeric Golgi (COG) complex is essential for the structure/function of the Golgi apparatus through regulation of membrane trafficking. Here, we describe a patient with a mild form of a congenital disorder of glycosylation type II (CDG-II), which is caused by a homozygous nonsense mutation in the hCOG8 gene. This leads to a premature stop codon resulting in a truncated Cog8 subunit lacking the 76 C-terminal amino acids. Mass spectrometric analysis of the N- and O-glycan structures identified a mild sialylation deficiency. We showed that the molecular basis of this defect in N- and O-glycosylation is caused by the disruption of the Cog1-Cog8 interaction due to truncation. As a result, Cog1 deficiency accompanies the Cog8 deficiency, preventing assembly of the intact, stable complex and resulting in the appearance of smaller subcomplexes. Moreover, levels of beta1,4-galactosytransferase were significantly reduced. The defects in O-glycosylation could be fully restored by transfecting the patient's fibroblasts with full-length Cog8. The Cog8 defect described here represents a novel type of CDG-II, which we propose to name as CDG-IIh or CDG caused by Cog8 deficiency (CDG-II/Cog8).

Adaptor Proteins, Vesicular Transport↗
PubMed2007

Intersectin is a negative regulator of dynamin recruitment to the synaptic endocytic zone in the central synapse.

Intersectin is a multidomain dynamin-binding protein implicated in numerous functions in the nervous system, including synapse formation and endocytosis. Here, we demonstrate that during neurotransmitter release in the central synapse, intersectin, like its binding partner dynamin, is redistributed from the synaptic vesicle pool to the periactive zone. Acute perturbation of the intersectin-dynamin interaction by microinjection of either intersectin antibodies or Src homology 3 (SH3) domains inhibited endocytosis at the fission step. Although the morphological effects induced by the different reagents were similar, antibody injections resulted in a dramatic increase in dynamin immunoreactivity around coated pits and at constricted necks, whereas synapses microinjected with the GST (glutathione S-transferase)-SH3C domain displayed reduced amounts of dynamin in the neck region. Our data suggest that intersectin controls the amount of dynamin released from the synaptic vesicle cluster to the periactive zone and that it may regulate fission of clathrin-coated intermediates.

Adaptor Proteins, Vesicular Transport↗