Delayed changes in neural visinin-like calcium-binding protein gene expression caused by acute phencyclidine administration

Summary Phencyclidine (PCP) induces a psychotomimetic state that closely resembles schizophrenia, and PCP-treated animals can serve as a model for schizophrenia. The effects of PCP on the gene expression of NVP-1, a novel Ca²⁺-binding protein, were studied in rats. After 24 hours, the NVP-1 mRNA level in the nucleus accumbens showed a significant decrease of 42%. This result suggests that alterations in Ca²⁺-binding protein may be involved in the pathology of PCP-induced psychosis and, presumably, schizophrenia.     

Hippocampal neurons in schizophrenia

Summary. The hippocampus is crucial for normal brain function, especially for the encoding and retrieval of multimodal sensory information. Neuropsychiatric disorders such as temporal lobe epilepsy, amnesia, and the dementias are associated with structural and functional abnormalities of specific hippocampal neurons. More recently we have also found evidence for a role of the hippocampus in the pathophysiology of schizophrenia. The most consistent finding is a subtle, yet significant volume difference in schizophrenia. Here we review the cellular and molecular basis of smaller hippocampal volume in schizophrenia. In contrast to neurodegenerative disorders, total hippocampal cell number is not markedly decreased in schizophrenia. However, the intriguing finding of a selective loss of hippocampal interneurons deserves further study. Two neurotransmitter receptors, the GABAA and AMPA/kainate glutamate receptors, appear to be abnormal, whereas changes of the NMDA glutamate receptor are less robust. The expression of several genes, including those related to the GABAergic system, neurodevelopment, and synaptic function, is decreased in schizophrenia. Taken together, recent studies of hippocampal cell number, protein expression, and gene regulation point towards an abnormality of hippocampal architecture in schizophrenia. Received February 21, 2002; accepted March 1, 2002     

Expression of the neuronal calcium sensor protein NCS-1 in the developing mouse olfactory pathway

Neuron specific calcium sensor 1 (NCS-1) is widely expressed in the developing and adult nervous system. Like calmodulin, NCS-1 is a member of a family of calcium binding proteins that contain EF-hand motifs, which bind calcium and induce conformational changes in the protein. Their binding varies with calcium concentration, allowing them to act as true calcium sensors rather than just calcium binding proteins. This family of proteins has been implicated in important synaptic events including neurotransmitter release and synapse formation. We examined the expression of NCS-1 in the developing and mature olfactory system to determine whether this molecule may be playing a role in establishing and/or maintaining olfactory circuitry. During development, expression of NCS-1 in the olfactory epithelium was localized in the dendritic knobs and axons of olfactory sensory neurons. Axonal expression was down-regulated after synapse formation. In the developing olfactory bulb, NCS-1 was expressed in the processes of mitral/tufted and granule cells. However, in the adult olfactory bulb, strongest expression was found in a subset of periglomerular cells (PGCs). This subset of PGCs did not express other known markers of PGCs including tyrosine hydroxylase, glutamic acid decarboxylase, calbindin, or calretinin, and only partially overlapped with the subpopulation of PGCs that express parvalbumin. Together, these data suggest multiple and overlapping roles of NCS-1 in the developing and mature olfactory system.     

Hippocampal FGF-2 and FGFR1 mRNA expression in major depression, schizophrenia and bipolar disorder

INTRODUCTION: FGF-2 is important for stem cell proliferation, neocortical development and adult neuronal survival and growth. Reduced frontal cortical FGF-2 expression is described in major depression and is attenuated by antidepressants. We determined the distribution of hippocampal FGF-2 and its receptor (FGFR1) mRNA in post-mortem brains of people who suffered from major depression, bipolar disorder and schizophrenia and those of controls. METHODS: FGF-2 and FGFR1 mRNA were measured within hippocampal CA1, CA4 regions and the dentate gyrus (DG), using in situ hybridization. Within hippocampal regions, cellular staining was compared between diagnostic groups, using repeated measures analysis of variance. RESULTS: The density of FGF-2 mRNA+ cells in CA4 was reduced in depression compared to controls. The percentage of FGFR1 mRNA+ cells was higher in depression (CA1 and CA4) and schizophrenia (CA4) than in controls. FGFR1 mRNA expression was higher in depression than in the other groups in CA1, CA4 and DG. Overall FGF-2 mRNA expression was higher in DG than in CA1 and CA4. CONCLUSIONS: We found raised measures of FGFR1 mRNA+ in major depression and, less so, in schizophrenia, along with reduced FGF-2 mRNA density in depression. Perturbations of FGF regulation could be relevant to the pathogenesis of both disorders as FGF-2 and FGFR1 are implicated in normal hippocampal synaptology, stem cell recruitment, and connectivity, and are modulated by corticosteroids.     

脑梗死后认知障碍与血清视锥蛋白样蛋白-1水平及神经功能缺损关系的研究

目的探讨脑梗死后认知障碍与血清视锥蛋白样蛋白-1(VILIP-1)水平及神经功能缺损的相关性。方法收集120例急性脑梗死患者,根据蒙特利尔认知评估量表(Mo CA)测评结果分为认知障碍组和认知正常组,比较两组患者入院时和发病1年时血清VILIP-1水平、美国国立卫生研究院卒中量表(NIHSS)评分、Barthel指数(BI)评分,分析Mo CA分值与血清VILIP-1水平、NIHSS评分和BI评分的相关性。结果两组患者发病1年时NIHSS评分均低于入院时(P0.01);BI评分均高于入院时(P0.01)。认知障碍组入院时及发病1年时血清VILIP-1水平高于认知正常组(P0.01);NIHSS评分高于认知正常组(P0.01);BI评分低于认知正常组(P0.01)。入院时及发病1年时所有患者Mo CA分值与血清VILIP-1水平呈负相关(r=-0.736,P=0.000;r=-0.450,P=0.000);与NIHSS评分呈负相关(r=-0.575,P=0.000;r=-0.377,P=0.001);与BI评分呈正相关(r=0.431,P=0.000;r=0.483,P=0.000)。结论脑梗死后认知障碍与血清VILIP-1水平及神经功能的康复有重要相关性。     

Hippocampal benzodiazepine receptors in schizophrenia

Summary Benzodiazepine receptor sites were determined by saturable [³H]flunitrazepam binding in hippocampal tissue from schizophrenic and control subjects. No difference in receptor density or affinity between the two groups was observed, indicating that the previously identified GABAergic deficit in the hippocampus in schizophrenia does not apparently lead to up-regulation of these receptor sites. The implications of this finding are discussed.     

Hippocampal dysfunction in schizophrenia.

Although not necessarily primary to the disease, hippocampal dysfunction in schizophrenia is suggested by morphological changes in the hippocampal formation reported in schizophrenic patients. This notion receives additional support from studies showing that 1) similar behavioral deficits are exhibited by both schizophrenics and animals with hippocampal lesions, and 2) some of these behavioral deficits are reversed by neuroleptics in both schizophrenics and lesioned animals. A brain-mapped neural network model is used to explain how some impairments in attention can be caused by hippocampal dysfunction and ameliorated by dopaminergic blockers.     

Serum and cerebrospinal fluid levels of visinin-like protein-1 in acute encephalopathy with biphasic seizures and late reduced diffusion

Background: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) has recently been recognized as an encephalopathy subtype. Typical clinical symptoms of AESD are biphasic seizures, and MRI findings show reduced subcortical diffusion during clustering seizures with unconsciousness after the acute phase. Visinin-like protein-1 (VILIP-1) is a recently discovered protein that is abundant in the central nervous system, and some reports have shown that VILIP-1 may be a prognostic biomarker of conditions such as Alzheimer’s disease, stroke, and brain injury. Methods: However, there have been no reports regarding serum and cerebrospinal fluid (CSF) levels of VILIP-1 in patients with AESD. We measured the serum and CSF levels of VILIP-1 in patients with AESD, and compared the levels to those in patients with prolonged febrile seizures (FS). Results: Both serum and CSF levels of VILIP-1 were significantly higher in patients with AESD than in patients with prolonged FS. Serum and CSF VILIP-1 levels were normal on day 1 of AESD. Conclusions: Our results suggest that both serum and CSF levels of VILIP-1 may be one of predictive markers of AESD.     

Increased expression of calcium/calmodulin-dependent protein kinase IIbeta in frontal cortex in schizophrenia and depression

In searching for genes dysregulated in schizophrenia, we measured the expression of the two splice variants of calcium/calmodulin-dependent protein kinase II (CaMKIIalpha and CaMKIIbeta) in postmortem frontal cerebral cortex tissues from patients who had died with schizophrenia, bipolar disorder, or severe depression. The mRNA levels of expression of these two splice variants were measured by real-time Quantitative PCR, using an Mx4000 instrument. The values for the expression of CaMKIIalpha and CaMKIIbeta were normalized by the expression of beta-glucuronidase in the tissues. The expression of CaMKIIalpha was significantly elevated in the depression tissues by 29%. The expression of CaMKIIbeta was significantly elevated in the schizophrenia tissues by 27%, and in the depression tissues by 36%. Because CaMKIIbeta influences the expression of many neuroreceptors and influences neural outgrowth and pruning, its altered expression in the cerebral cortex in schizophrenia or depression may contribute to these diseases.     

Abnormal localization of two neuronal calcium sensor proteins, visinin-like proteins (vilips)-1 and -3, in neocortical brain areas of Alzheimer disease patients

The anatomical distribution of the neuronal calcium sensor proteins visinin-like protein-1 and -3 (VILIP-1 and -3) was investigated in various neocortical areas of Alzheimer's disease (AD) patients and controls. In AD and normal brains their cellular localization was confined to pyramidal and non-pyramidal neurons. In AD brains the intracellular immunostaining for VILIP-1 and to a lesser extent for VILIP-3 was found to be reduced in comparison to controls. Also, significantly less VILIP-1-immunoreactive neurons were found in the temporal cortex of AD patients as compared to normal brains. Accordingly, Western blot analysis revealed that immunoreactivity for VILIP-1 is less concentrated in tissue extracts of the temporal cortex of AD patients compared to controls. Extracellularly, VILIP-1 and VILIP-3 immunoreactive material was detected in close association with typical pathologic hallmarks of AD such as dystrophic nerve cell processes, amorphous and neuritic plaques, and extracellular tangles. In control brains an extraneuronal localization of VILIP-1 or VILIP-3 was never observed. Our morphological and neurochemical findings point to an involvement of these two neuronal calcium sensor proteins in pathology and possibly pathophysiology of changed calcium homeostasis in AD.     

Hippocampal deformities in the unaffected siblings of schizophrenia subjects.

BACKGROUND: Neuroanatomical abnormalities have been reported in schizophrenia subjects and their relatives and may be related to genetic vulnerability. The objective of this study was to further elucidate hippocampal deformities as a marker of genetic vulnerability for schizophrenia. METHODS: Magnetic resonance scans were collected in 13 pairs of schizophrenics and their unaffected siblings from families with multiple affected members, in 12 schizophrenics from families without another affected member, and in 10 healthy controls. Hippocampal volume and shape were compared using large-deformation high-dimensional brain mapping. RESULTS: Decreases in hippocampal volume, covaried for total cerebral volume, were observed in the schizophrenia subjects from families with multiple affected members, as well as in their unaffected siblings. Shape analysis demonstrated that both groups of schizophrenia subjects, as well as the unaffected siblings, could be distinguished from the controls; however, no significant difference in hippocampal shape was found between the schizophrenia subjects and their unaffected siblings. Visualization of the pattern of hippocampal shape deformity in both groups of schizophrenia subjects and in the unaffected siblings showed inward deformities of the head of the hippocampus. CONCLUSIONS: Deformations of hippocampal anatomy may be related to the genetic vulnerability of acquiring schizophrenia.     

Hepatic consequences of vascular adhesion protein-1 expression

The liver is constantly exposed to antigens present in the blood and to particulate antigens delivered from the gut. To maintain effective levels of immune surveillance and yet tolerate food antigens, the hepatic environment has become highly specialised. A low flow environment exists within the hepatic sinusoids that not only facilitates the exchange of toxins and nutrients within the liver parenchyma, but also provides an ideal niche for the recruitment of leukocytes. One such adhesion molecule involved in this process, the vascular adhesion protein-1 (VAP-1), is unusual in the context of the leukocyte adhesion cascade in that it is both an adhesion molecule and a primary amine oxidase. In this review, we examine the biological functions of VAP-1 and examine what role this molecule might play in the establishment and progression of chronic liver disease.     

DTNBP1基因与精神分裂症

目的:了解DTNBP1基因与精神分裂症的连锁关系.方法:选取DTNBP1基因附近的微卫星标志D6s 289,对81个符合美国精神障碍诊断与统计手册第4版诊断标准的精神分裂症受累同胞对及 家系成员共324个个体作基因分型,其中男166例,女158例,患病同胞对81对162例.对分型资料进行非参数连锁分析和传递不平衡分析.结果:两点非参数分析Lod值为0.697 57(P=0.264 885),传递不平衡分析无阳性发现.结论:未能肯定DTNBP1基因是否为精神分裂症的易感基因之一.     

Hippocampal volume and the AKT signaling system in first-episode schizophrenia

ObjectiveThe phosphoinositide 3′-kinase (PI3K) – protein kinase B (AKT1) – glycogen synthase kinase (GSK)-3β system is modulated by several factors implicated in the pathophysiology of schizophrenia. Evidence suggests that neuregulin 1 (NRG1) induces decreased AKT phosphorylation in schizophrenia relative to healthy controls, which may be related to dysfunctional neurodevelopment and neuroplasticity. The aim of this study was to investigate the relationship between NRG1 – induced AKT phosphorylation and hippocampal volume in schizophrenia.MethodsParticipants were 20 first-episode patients with schizophrenia who did not receive psychotropic medications and 20 matched healthy controls. We measured the phosphorylated AKT – total AKT and phosphorylated ERK (extracellular signal-regulated kinase) – total ERK ratios in peripheral lymphoblasts before and after NRG1 administration. Whole-brain, left, and right hippocampal volumes were quantified using FreeSurfer software.ResultsPatients with schizophrenia displayed decreased AKT but normal ERK ratio compared with controls. Patients also had a reduction in left hippocampal volume. There was no significant difference between patients and controls in whole-brain and right hippocampal volume. Decreased AKT ratio was associated with reduced hippocampal volume. There was no significant relationship between ERK ratio and brain structure.ConclusionActivation of the AKT system is specifically associated with hippocampal volume in first-episode schizophrenia, which provides further evidence for the pivotal role of this messenger system in the pathophysiology of psychotic disorders.     

Hippocampal complexin proteins and cognitive dysfunction in schizophrenia

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.     

Hippocampal volume in first-episode schizophrenia and longitudinal course of the illness

Objectives: Several lines of evidence suggest an adverse effect of psychotic episodes on brain morphology. It is not clear if this relationship reflects the cumulative effect of psychotic outbursts on the gradual progressive reduction of hippocampal tissue or an increased tendency toward psychotic episodes in patients with a smaller hippocampus at the beginning of the illness.

Methods: This is a longitudinal 4-year prospective study of patients with first-episode schizophrenia (FES, N?=?58). Baseline brain anatomical scans (at FES) were analysed using voxel-based morphometry and atlas-based volumetry of the hippocampal subfields. The effects of first-episode duration on the hippocampal morphology, and the effect of baseline hippocampal morphology on illness course with relapses, number of psychotic episodes and residual symptoms were analysed.

Results: A significant negative correlation was detected between first-episode duration and baseline hippocampal morphology. Relapse, number of psychotic episodes and residual symptoms had no correlation with baseline hippocampal volume.

Conclusions: We replicated the effect of psychosis duration on hippocampal volume already at the time first-episode, which supports the concept of toxicity of psychosis. The indices of a later unfavourable course of schizophrenia had no correlation with baseline brain morphology, suggesting that there is no baseline morphological abnormality of the hippocampus that predisposes the patient to frequent psychotic outbursts.     

Alterations in hippocampal non-phosphorylated MAP2 protein expression in schizophrenia

Microtubule-associated proteins (MAPs) are central to the development of normal neuronal cytoarchitecture and have been suggested in previous studies to be altered in schizophrenia. We investigated hippocampal phosphorylated and non-phosphorylated MAP2 expression in schizophrenia in relation to neuronal orientation and interneuronal distance. One paraffin embedded mid-hippocampal block was obtained from each of 8 schizophrenic and 11 control postmortem brains and immunohistochemistry for the phosphorylated and non-phosphorylated forms of MAP2 performed. Within the corona ammonis (CA) subregions and the subiculum, we assessed densitometry readings for non-phosphorylated MAP2-positive neurones (MAP2-NP), and counted the number of neurones immunopositive for phosphorylated MAP2 (MAP2-P). Using image analysis computer software we measured interneuronal distances and neuronal orientation. While there were no overall alterations in densitometric density of MAP2-NP neurones in any hippocampal subregions, we found a left-sided increase in densitometric density of MAP2-NP neurones within the subiculum (F=8.740, P<0.021), and the CA1 (F=7.044, P<0.033) of schizophrenic subjects which were unrelated to age, postmortem interval or neuroleptic exposure. There was no accompanying alteration of interneuronal distances, neuronal orientation. The findings support previous work demonstrating altered subicular MAP2 expression in schizophrenia and indicate that the finding may be lateralised. However, in contrast to previous investigations, we have demonstrated this alteration in MAP2 expression is due to an increase in the non-phosphorylated form of MAP2, rather than a decrease in total MAP2 expression. These findings suggest that cytoskeletal assembly is abnormal in schizophrenia and generate testable hypotheses regarding the developmental basis of the disorder.     

Serine racemase protein expression in cortex and hippocampus in schizophrenia

Evidence of glutamatergic dysfunction in schizophrenia associated with the N-methyl-D-aspartate receptor has historically demonstrated changes primarily attributable to neurons. We propose an astrocytic component to N-methyl-D-aspartate receptor dysfunction in this illness. We studied the expression of serine racemase, an astrocytic enzyme which synthesizes the N-methyl-D-aspartate receptor coagonist D-serine, using Western blot analysis in postmortem hippocampus and cortex in schizophrenia and a comparison group. We found increased expression in the hippocampus in schizophrenia. This is the first study to demonstrate alterations in schizophrenia of an astrocytic enzyme responsible for synthesizing a neuromodulator, and further evidence that astrocytes may play a direct role in N-methyl-D-aspartate receptor dysfunction in schizophrenia.