Cell-type specific alterations of cortical interneurons in schizophrenic patients

In the human brain, cortical GABAergic interneurons represent an important population of local circuit neurons responsible for the intrinsic modulation of neuronal information and have been supposed to be involved in the pathophysiology of schizophrenia. We conducted a quantitative study on the differentiated three-dimensional morphological structure of two types of parvalbumin-immunoreactive interneurons in the anterior cingulate cortex (ACC) of schizophrenic patients versus controls. While type A interneurons ('small bipolar cells') showed a significant reduction of their soma size in schizophrenics, type B interneurons ('small multipolar cells') of schizophrenic patients exhibited a marked decrease in the extent of their dendritic system. These results further support the assumption of a considerable significance of the ACC, an important limbic relay centre, for the etiopathogenesis of schizophrenic psychoses.     

精神分裂症患者的性激素分泌变异

为研究精神分裂症患者垂体促性腺激素及外周性激素的功能状态，探讨性激素水平改变与性有关症状和药物治疗的关系，采用放射免疫法测定６０例（男４０例，女２０例）精神分裂症患者的血清促卵泡激素（ＦＳＨ）、黄体生成素（ＬＨ）、催乳素（ＰＲＬ）、睾丸酮（Ｔ）、雌二醇（Ｅ２）等激素水平，并与２０名（男女各１０名）正常人对照。结果显示，试验组中男性ＬＨ和女性ＰＲＬ水平明显低于对照组，女性患者的Ｔ与Ｅ２水平显著升高。按性有关症状的有无分为两组，两组间性激素水平无显著性差异。药物治疗前后男患者ＰＲＬ，女患者ＦＳＨ、ＰＲＬ、Ｔ和Ｅ２等激素分泌改变非常显著。氯丙嗪、舒必利可致明显的高ＰＲＬ血症，但氯氮平无明显影响。提示精神分裂症患者性腺轴存在功能失调。性有关症状与性激素水平改变无关。抗精神病药治疗可导致性激素分泌紊乱。     

Membrane phospholipid abnormalities in postmortem brains from schizophrenic patients

Previous studies in schizophrenia have shown alterations in membrane phospholipids and polyunsaturated fatty acids. However, these studies have primarily examined peripheral (non-neuronal) cell types. The purpose of the present study was to examine whether the membrane deficits seen in peripheral tissues are also observed in the brain. The caudate was the primary region of interest for this study. Using high-pressure liquid chromatography in conjunction with an evaporative light-scattering detector, we first measured the level of various membrane phospholipids (PL) in schizophrenic (n=11) and control groups with (n=7) and without (n=14) other mental disorders. Polyunsaturated fatty acids (PUFAs) were then determined by capillary gas chromatography. Within groups, there are no significant correlations between membrane PL levels and other collection and demographic parameters including age, postmortem interval, storage time and brain weight. Significantly lower amounts of phosphatidylcholine and phosphatidylethanolamine were found in postmortem brain tissue from schizophrenic patients than in those from control groups, even after accounting for potential confounds. In addition, strong reductions of total PUFAs and saturated fatty acids were found in schizophrenic brains, relative to control brains. Specifically, the reduced PUFAs were largely attributable to decreases in arachidonic acid (AA) and, to a lesser extent, its precursors, linoleic and eicosadienoic acids. There are no significant differences between the control groups with and without other mental disorders. The present findings suggest that deficits identified in peripheral membranes may also be present in the brain from schizophrenic patients. Such a deficit in membrane AA may contribute to the many biological, physiological, and clinical phenomena observed in schizophrenia.     

Cognitive abnormalities in schizophrenic patients and schizotypal college students

Twenty schizotypal college students, identified by the MMPI-168, were compared with 127 institutionalized or postinstitutional psychiatric patients with chronic schizophrenia, 140 normal control subjects, and 19 students with nonschizotypal MMPI elevations. The comparison measures were indices of cognition derived from COGLAB, a multiparadigmatic cognitive test battery. COGLAB includes measures of preattentional, attentional, conceptual, and psychomotor performance. As expected, the patients were deficient on all but one of the measures. The nonschizotypic elevation group was not different from the normal control group. Schizotypal subjects were found to have deficits in three areas of information processing: preattentional processing, response biasing, and concept attainment and manipulation. However, their performance was just as good as and less variable than that of normal subjects on psychomotor and attentional tasks. The results do not support the hypothesis that schizotypy is characterized by pervasive cognitive deficits which are simply less severe than those of other psychiatric groups. Rather, there are discrete deficits in specific areas and possibly compensatory abnormalities associated with primary deficits. The results are further discussed with regard to the hypothesis that schizotypy shares a common neurophysiological and/or developmental substrate with more severe psychiatric disorders.     

Re-emergence of striatal cholinergic interneurons in movement disorders

Twenty years ago, striatal cholinergic neurons were central figures in models of basal ganglia function. But since then, they have receded in importance. Recent studies are likely to lead to their re-emergence in our thinking. Cholinergic interneurons have been implicated as key players in the induction of synaptic plasticity and motor learning, as well as in motor dysfunction. In Parkinson's disease and dystonia, diminished striatal dopaminergic signalling leads to increased release of acetylcholine by interneurons, distorting network function and inducing structural changes that undoubtedly contribute to the symptoms. By contrast, in Huntington's disease and progressive supranuclear palsy, there is a fall in striatal cholinergic markers. This review gives an overview of these recent experimental and clinical studies, placing them within the context of the pathogenesis of movement disorders.     

Familial aspects of CT scan abnormalities in chronic schizophrenic patients

To investigate the possibility that lateral cerebral ventricular size may be under genetic control, we compared the computed tomography (CT) scans of 17 healthy siblings from 7 normal sibships. The CT scans of 10 chronic schizophrenic patients and 12 of their nonschizophrenic siblings were also compared. A trend was found for a correlation of ventricular size between siblings in the healthy sibships (ICC = 0.25, p = 0.1) but not in the schizophrenic sibships (ICC = -0.05). In each sibship the schizophrenic patient had the largest ventricles; in seven cases they exceeded the normal range. Although the discordant siblings were all well within the normal range, their ventricles were larger (p = 0.001) than those of the controls. The findings suggest a genetic component to ventricular size in healthy individuals and that CT findings in schizophrenics are not coincidental familial traits but markers of the illness. The implications of the findings in the discordant siblings are discussed.     

Excitatory extrinsic afferents to striatal interneurons and interactions with striatal microcircuitry

The striatum constitutes the main input structure of the basal ganglia and receives two major excitatory glutamatergic inputs, from the cortex and the thalamus. Excitatory cortico‐ and thalamostriatal connections innervate the principal neurons of the striatum, the spiny projection neurons (SPNs), which constitute the main cellular input as well as the only output of the striatum. In addition, corticostriatal and thalamostriatal inputs also innervate striatal interneurons. Some of these inputs have been very well studied, for example the thalamic innervation of cholinergic interneurons and the cortical innervation of striatal fast‐spiking interneurons, but inputs to most other GABAergic interneurons remain largely unstudied, due in part to the relatively recent identification and characterization of many of these interneurons. In this review, we will discuss and reconcile some older as well as more recent data on the extrinsic excitatory inputs to striatal interneurons. We propose that the traditional feed‐forward inhibitory model of the cortical input to the fast‐spiking interneuron then inhibiting the SPN, often assumed to be the prototype of the main functional organization of striatal interneurons, is incomplete. We provide evidence that the extrinsic innervation of striatal interneurons is not uniform but shows great cell‐type specificity. In addition, we will review data showing that striatal interneurons are themselves interconnected in a highly cell‐type‐specific manner. These data suggest that the impact of the extrinsic inputs on striatal activity critically depends on synaptic interactions within interneuronal circuitry.     

Neuromorphological abnormalities in schizophrenic patients with good and poor outcome

OBJECTIVE: The present study was designed specifically to assess the relationship between brain morphology and outcome in schizophrenia. METHOD: Fifty-six schizophrenic patients and a matched group of 32 healthy subjects were studied with magnetic resonance (MR) imaging scans. Clinical assessment included the Krawiecka-Manchester Scale (K-MS) and the Outcome scale by Strauss and Carpenter. RESULTS: Along several neuromorphological measures the patients differed from controls only for right and left ventricular volumes. The 'poor outcome' patients had a left and right ventricular enlargement when compared to the 'good outcome' patients and healthy controls. A regression analysis showed that right ventricle volume, left temporal lobe volume and left hippocampal volume entered into the regression equation, accounting for a 27% of the outcome measure. CONCLUSION: The outcome does not seem to be predicted by one particular morphological site but involves different brain regions; however, the ventricular enlargement identifies a subgroup of patients with poor outcome.     

A retrospective study of clozapine and electroencephalographic abnormalities in schizophrenic patients

This study investigated the incidence and nature of clozapine-associated electroencephalographic (EEG) abnormalities and the relationship between EEG abnormality and clozapine dosage in Korean schizophrenic patients. Fifty schizophrenic patients with normal baseline EEG and with additional EEG record examined during clozapine treatment more than once were included. Thirty-one patients (62%) showed abnormal EEGs after clozapine treatment, and two of them had seizures. The majority of EEG abnormalities presented as nonspecific slow waves (SW). Spikes (or spike and wave complexes; SP) and frontal intermittent rhythmic delta activity (FIRDA) were relatively rarely observed. The probability of EEG abnormality was linearly dependent on the daily dose of clozapine and patient's age. Our results can be summarized as follows: (1) a substantial proportion of Korean patients treated with clozapine develops EEG abnormalities, and its incidence is comparable to the published results in Caucasian patients; (2) EEG abnormalities occurred in a dose-dependent manner; and (3) the occurrence of EEG abnormalities did not necessarily lead to future seizure development, except in a small number of cases.     

The importance of interneurons in schizophrenic and affective disorders

In brains of patients with schizophrenic and affective disorders pathomorphological changes have been shown focussing in frontal and temporal cortex. The volume reduction in prefrontal cortex of schizophrenic patients is hypothesized to be based on a reduction of neuropil. A decrease of synaptic proteins and a decrease of dendritic spines of pyramidal cells can additionally be the origin of disconnections of neurons. Affection of the glutamatergic, GABA-ergic and dopaminergic system and reduction of interneurons could be the correlate of a deficient neuronal network which might be combined with exogen factors generate psychotic symptoms. Reelin and associated proteins are candidate molecules. Their dysregulation might explain essential features of the dysfunctional network of schizophrenia.     

Structural abnormalities in the cerebral cortex of chronic schizophrenic patients.

Enlarged cerebral ventricles in chronic schizophrenic patients suggest a process of mild cerebral atrophy occurs in some. To see if this process involves the cerebral cortex, the widths of the Sylvian fissure, the interhemispheric fissure, and three cortical sulci were measured blindly on computerized tomography (CT) scans of 75 chronic psychiatric patients and 62 asymptomatic volunteers, all less than 50 years of age. A total of 19 of the 60 patients with chronic schizophrenia had at least one abnormality. All 15 patients with other diagnoses were within the control range. Comparing those chronic schizophrenic patients with abnormalities to those without them, there were no significant differences in age, length of illness or treatment, and length of hospitalization. From this and ventricular size data, two thirds of the chronic schizophrenics had some cerebral structural abnormality. Ventricular enlargement did not correlate significantly with cortical abnormalities. Therefore, more than one etiology may account for the structural abnormalities found in chronic schizophrenic patients.     

Selective inhibition of striatal fast-spiking interneurons causes dyskinesias

Fast-spiking interneurons (FSIs) can exert powerful control over striatal output, and deficits in this cell population have been observed in human patients with Tourette syndrome and rodent models of dystonia. However, a direct experimental test of striatal FSI involvement in motor control has never been performed. We applied a novel pharmacological approach to examine the behavioral consequences of selective FSI suppression in mouse striatum. IEM-1460, an inhibitor of GluA2-lacking AMPARs, selectively blocked synaptic excitation of FSIs but not striatal projection neurons. Infusion of IEM-1460 into the sensorimotor striatum reduced the firing rate of FSIs but not other cell populations, and elicited robust dystonia-like impairments. These results provide direct evidence that hypofunction of striatal FSIs can produce movement abnormalities, and suggest that they may represent a novel therapeutic target for the treatment of hyperkinetic movement disorders.     

Deficits in small interneurons in prefrontal and cingulate cortices of schizophrenic and schizoaffective patients.

A recent report suggested that neurons in the prefrontal, anterior cingulate, and primary motor cortex of the brains of schizophrenic subjects may be less dense than those in the brains of nonschizophrenic subjects. We have determined whether pyramidal neurons and/or interneurons are preferentially reduced in schizophrenic subjects. Twelve control subjects and 18 schizophrenic subjects were studied in a blind, quantitative analysis of the density of pyramidal cells, interneurons, and glial cells in each of the six layers of the anterior cingulate and prefrontal cortex. The results showed that numbers of small neurons (interneurons) were reduced in most layers of the cingulate cortex in schizophrenic subjects compared with nonschizophrenic subjects, with the differences being greatest in layer II. In the prefrontal area, interneuronal density was also lower in layer II and, to a lesser extent, in layer I in schizophrenic subjects compared with control subjects. In most cases, the differences were similar, although more significant, in schizophrenic subjects who had had superimposed mood disturbances than in schizophrenic subjects who had not had such comorbidity. Numbers of pyramidal neurons generally were not different between control and schizophrenic subjects, except in layer V of the prefrontal area, where schizophrenic subjects showed higher densities of these neurons. Glial numbers did not differ between the control and schizophrenic subjects, suggesting that a neurodegenerative process did not cause the reduced interneuronal density observed. Using multiple regression analysis and analysis of covariance, decreases in the density of layer II interneurons could not be adequately explained by the effects of various confounding variables, such as age, postmortem interval, duration of specimen fixation, or administration of neuroleptic agents.(ABSTRACT TRUNCATED AT 250 WORDS)     

Adenylate cyclase in striatal cholinergic interneurons regulates acetylcholine release

Fractional [³H]ACH efflux from dissociated rat striata tested whether tonic inhibition prevents stimulation of acetylcholine (ACH) release by adenylate cyclase. Forskolin stimulated release from the dissociated cells (threshold at 300 nM; EC₅₀ ≥ 1 μM). Release was also stimulated by 3-isobutyl-l-methylxanthine and was additive with forskolin. The 1,9-dideoxy forskolin analog that lacks cyclase-stimulating activity was ineffective. Thus, stimulation of adenylate cyclase within striatal cholinergic interneurons increases ACH secretion but is tonically inhibited by endogenous striatal transmitters. Disinhibition of the excitatory cyclase by denervation of striatal cholinergic interneurons in situ could contribute to supersensitivity without receptor upregulation.     

Basic symptoms and P300 abnormalities in young schizophrenic patients.

Among the reasons for the relatively limited number of investigations of self-knowledge phenomena should be included, in addition to theoretical motives, the difficulties regarding the use of instruments available for this kind of approach and their content validity. This study investigates the relationship between subjective and objective deficits in schizophrenia, taking into account subjective experiences of cognitive impairment, clinical symptoms, and cognitive evoked potentials (P300 component). A group of 36 young schizophrenic patients (29 on neuroleptic treatment and seven drug-naive) were considered, together with a comparison group of 36 healthy subjects. Auditory event-correlated potentials (ERPs) were obtained using a simple "oddball" paradigm. Clinical symptoms were rated with the Brief Psychiatric Rating Scale (BPRS) and Scales for the Assessment of Positive and Negative Symptoms (SAPS and SANS), and while subjective disturbances were assessed by the Frankfurter Beschwerde Fragebogen (FBF, also called the Complaint Questionnaire). Correlation analysis showed that P300 amplitude was inversely correlated with subjective experiences of cognitive deficit, especially in the area of automatic skills and overstimulation. No relationship emerged between BPRS, SANS, and SAPS scores and P300 alterations. The results suggest that subjective cognitive disturbances, more than objective symptoms, are related to P300 alterations in schizophrenia, and that the FBF questionnaire appropriately covers the domain of schizophrenic cognitive disorders.     

Neurological abnormalities in schizophrenic twins.

BACKGROUND: Neurological abnormalities (NAs) are well recognized in schizophrenia, though their genetic and environmental determinants, and pathophysiological significance, are poorly understood. METHODS: Sixty-three twin pairs, varying in their zygosity and concordance for schizophrenia, and 73 unaffected control twin pairs were examined for total, primary and integrative NAs using the Neurological Evaluation Scale. RESULTS: NAs were increased in probands with schizophrenia compared to nonschizophrenic co-twins and to healthy control twins but there were no significant differences between patients from the concordant and discordant pairs. NAs in the nonpsychotic co-twins from discordant pairs were increased compared to control twins. There were no significant differences in NAs between the nonschizophrenic co-twins from monozygotic (MZ) and dizygotic (DZ) discordant pairs, but the within pair correlations were greater in the MZ compared to DZ pairs. NAs were modified in all groups by pre-morbid schizotypal traits, and in patients by anti-psychotic medication. CONCLUSIONS: NAs in schizophrenia are determined in part by genetic risk for the illness but the presence of premorbid schizotypal traits, and anti-psychotic medication confer additional risk for NAs.     

Ablation of striatal interneurons influences activities of entopeduncular neurons

To characterize modulatory effects of striatal interneurons upon the output nucleus of the basal ganglia, we ablated striatal interneurons that express substance P receptors by using local injection of a selective neurotoxin, substance P-saporin, in rats. We then made extracellular recordings of the activity of entopeduncular neurons and examined their responses to stimulation in the motor cortex. In the interneuron-ablated animals, the spontaneous discharge rate of entopeduncular neurons was significantly decreased, and the proportion of entopeduncular neurons showing responses to cortical stimulation was significantly larger, in comparison with intact animals. It is suggested that striatal interneurons expressing substance P receptors are important for motor control mechanisms mediated by the cortico-basal ganglia pathways.     

TRPC3 channel mediates excitation of striatal cholinergic interneurons

Striatal cholinergic interneurons exhibit tonic firing and more positive membrane potentials, however, the mechanism is unclear. In the present study, we found that intracellular perfusion of TRPC3 antibody induced outward current in striatal cholinergic interneurons identified by electrophysiological characteristics. The TRPC3 channel blocker flufenamic acid induced hyperpolarization, and reduced firing rate and outward current which was similar to the effect of TRPC3 channel antibody. Furthermore, by using single-cell RT-PCR we confirmed the co-existence of TRPC3 channel and D5 receptor mRNA in striatal cholinergic interneurons identified by electrophysiological characteristics and expression of choline acetyltransferase (Chat) mRNA. These results implied that the TRPC3 channel is involved in modulating the depolarization of cholinergic interneurons.     

Multiple neuromuscular abnormalities in a paranoid schizophrenic

A broad range of skeletal muscle fiber abnormalities has been reported previously in muscle biopsy specimens from psychotic patients. In our experience, individual patients manifest only a few types of lesions; but we now have studied a paranoid schizophrenic patient whose skeletal muscle fibers show virtually the entire range of morphologic abnormalities. In addition to the morphologic abnormalities of skeletal muscle fibers, we also noted increases branching of subterminal motor nerves with enlarged endplates and chronic elevations of serum creatine phosphokinase activity. Despite this, the patient had minimal clinical evidence of neuromuscular dysfunction. The variety of types of neuromuscular dysfunctions found in this patient suggests their etiology may be related.