ABSTRACT
Many studies implicate mitochondrial dysfunction as a key contributor to cell loss in Parkinson disease (PD). Previous analyses of dopaminergic (DAergic) neurons from patients with Lewy-body pathology revealed a deficiency in nuclear-encoded genes for mitochondrial respiration, many of which are targets for the transcription factor estrogen-related receptor gamma (Esrrg/ERRγ). We demonstrate that deletion of ERRγ from DAergic neurons in adult mice was sufficient to cause a levodopa-responsive PD-like phenotype with reductions in mitochondrial gene expression and number, that partial deficiency of ERRγ hastens synuclein-mediated toxicity, and that ERRγ overexpression reduces inclusion load and delays synuclein-mediated cell loss. While ERRγ deletion did not fully recapitulate the transcriptional alterations observed in postmortem tissue, it caused reductions in genes involved in synaptic and mitochondrial function and autophagy. Altogether, these experiments suggest that ERRγ-deficient mice could provide a model for understanding the regulation of transcription in DAergic neurons and that amplifying ERRγ-mediated transcriptional programs should be considered as a strategy to promote DAergic maintenance in PD.
ABSTRACT
An efficient technique for writing 2D oxide patterns on conductive substrates is proposed and demonstrated in this paper. The technique concerns a novel concept for selective electrodeposition, in which a minimum quantity of liquid electrolyte, through an extrusion nozzle, is delivered and manipulated into the desired shape on the substrate, meanwhile being electrodeposited into the product by an applied voltage across the nozzle and substrate. Patterns of primarily Cu2O with 80~90% molar fraction are successfully fabricated on stainless steel substrates using this method. A key factor that allows the solid product to be primarily oxide Cu2O instead of metal Cu - the product predicted by the equilibrium Pourbaix diagram given the unusually large absolute deposition voltage used in this method, is the non-equilibrium condition involved in the process due to the short deposition time. Other factors including the motion of the extrusion nozzle relative to the substrate and the surface profile of the substrate that influence the electrodeposition performance are also discussed.
ABSTRACT
Schizophrenia (SZ) is a mental illness characterized by psychosis, negative symptoms, and cognitive deficits. The anterior cingulate cortex (ACC), a structurally and functionally diverse region, is one of several brain regions that is abnormal in SZ. The present study compared synaptic organization and mitochondrial number and morphology in postmortem ACC in SZ versus normal control (NC). Total synaptic density in the combined ACC was decreased in SZ, to 72% of normal controls (NCs), due to selective decreases in axospinous synapses, both asymmetric (excitatory) and symmetric (inhibitory). These changes were present in layers 3 and 5/6. The density of mitochondria in all axon terminals combined in SZ was decreased to 64% of NC. In layer 3, mitochondrial density was decreased only in terminals forming asymmetric synapses with spines, while in layers 5/6 mitochondrial density was decreased in terminals forming symmetric synapses with spines and dendrites. The proportion of terminals making symmetric synapses that contained mitochondria was significantly lower in SZ than in NCs, especially for symmetric axospinous synapses. The number of mitochondria per neuronal somata was decreased in the ACC in SZ compared to NCs; this finding was present in layers 5-6. The size of mitochondria in neuronal somata and throughout the neuropil was similar in SZ and NCs. Our results, though preliminary, are well supported by the literature, and support an anatomical substrate for some of the altered executive functions found in SZ.
Subject(s)
Gyrus Cinguli/ultrastructure , Mitochondria/ultrastructure , Schizophrenia/pathology , Synapses/ultrastructure , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Microscopy, Electron , Middle AgedABSTRACT
The process of glutamate release, activity, and reuptake involves the astrocyte, the presynaptic and postsynaptic neurons. Glutamate is released into the synapse and may occupy and activate receptors on both neurons and astrocytes. Glutamate is rapidly removed from the synapse by a family of plasma membrane excitatory amino acid transporters (EAATs), also localized to neurons and astrocytes. The purpose of the present study was to examine EAAT labeling in the postmortem human cortex at the light and electron microscopic (EM) levels. The postmortem prefrontal cortex was processed for EAAT1 and EAAT2 immunohistochemistry. At the light microscopic level, EAAT1 and EAAT2 labeling was found in both gray and white matter. Most cellular labeling was in small cells which were morphologically similar to glia. In addition, EAAT1-labeled neurons were scattered throughout, some of which were pyramidal in shape. At the EM level, EAAT1 and EAAT2 labeling was found in astrocytic soma and processes surrounding capillaries. EAAT labeling was also found in small astrocytic processes adjacent to axon terminals forming asymmetric (glutamatergic) synapses. While EAAT2 labeling was most prevalent in astrocytic processes, EAAT1 labeling was also present in neuronal processes including the soma, axons, and dendritic spines. Expression of EAAT1 protein on neurons may be due to the hypoxia associated with the postmortem interval, and requires further confirmation. The localization of EAATs on the astrocytic plasma membrane and adjacent to excitatory synapses is consistent with the function of facilitating glutamate reuptake and limiting glutamate spillover. Establishment that EAAT1 and EAAT2 can be measured at the EM level in human postmortem tissues will permit testing of hypotheses related to these molecules in diseases lacking analogous animal models.
Subject(s)
Excitatory Amino Acid Transporter 1/metabolism , Glutamate Plasma Membrane Transport Proteins/metabolism , Prefrontal Cortex/metabolism , Prefrontal Cortex/ultrastructure , Adult , Aged , Animals , Astrocytes/metabolism , Astrocytes/ultrastructure , Excitatory Amino Acid Transporter 1/genetics , Excitatory Amino Acid Transporter 2 , Female , Humans , Male , Mice, Knockout , Microscopy, Electron , Middle Aged , Neurons/metabolism , Neurons/ultrastructure , Prefrontal Cortex/blood supply , Species SpecificityABSTRACT
Many behavioral, physiological, and anatomical studies utilize animal models to investigate human striatal pathologies. Although commonly used, rodent striatum may not present the optimal animal model for certain studies due to a lesser morphological complexity than that of non-human primates, which are increasingly restricted in research. As an alternative, the tree shrew could provide a beneficial animal model for studies of the striatum. The gross morphology of the tree shrew striatum resembles that of primates, with separation of the caudate and putamen by the internal capsule. The neurochemical anatomy of the ventral striatum, specifically the nucleus accumbens, has never been examined. This major region of the limbic system plays a role in normal physiological functioning and is also an area of interest for human striatal disorders. The current study uses immunohistochemistry of calbindin and tyrosine hydroxylase (TH) to determine the ultrastructural organization of the nucleus accumbens core and shell of the tree shrew (Tupaia glis belangeri). Stereology was used to quantify the ultrastructural localization of TH, which displays weaker immunoreactivity in the core and denser immunoreactivity in the shell. In both regions, synapses with TH-immunoreactive axon terminals were primarily symmetric and showed no preference for targeting dendrites versus dendritic spines. The results were compared to previous ultrastructural studies of TH and dopamine in rat and monkey nucleus accumbens. Tree shrews and monkeys show no preference for the postsynaptic target in the shell, in contrast to rats which show a preference for synapsing with dendrites. Tree shrews have a ratio of asymmetric to symmetric synapses formed by TH-immunoreactive terminals that is intermediate between rats and monkeys. The findings from this study support the tree shrew as an alternative model for studies of human striatal pathologies.
Subject(s)
Neurons/enzymology , Neurons/ultrastructure , Nucleus Accumbens/enzymology , Nucleus Accumbens/ultrastructure , Tupaiidae/anatomy & histology , Tyrosine 3-Monooxygenase/analysis , Animals , Axons/chemistry , Axons/immunology , Axons/ultrastructure , Calbindins/metabolism , Cell Size , Dendrites/chemistry , Dendrites/genetics , Dendrites/ultrastructure , Female , Immunohistochemistry , Male , Microscopy, Electron , Models, Animal , Neurons/chemistry , Nucleus Accumbens/chemistry , Photomicrography , Species Specificity , Synapses/chemistry , Synapses/enzymology , Synapses/ultrastructure , Tupaiidae/metabolismABSTRACT
The glutamate system includes presynaptic glutamatergic terminals, complex post-synaptic densities found on diverse types of neurons expressing glutamate receptors, as well as glutamate transporters and enzymes that facilitate the glutamate/glutamine cycle. Abnormalities of this system have been implicated in schizophrenia based on an accumulating body of evidence from postmortem, imaging, and preclinical studies. However, recent work has suggested that astrocytes may have more than a bystander role in the synchronization of neuronal responses in the brain. Converging evidence suggests that extrasynaptic glutamate microdomains are formed by astrocytes and may facilitate neuroplasticity via the modulation of extra-synaptic glutamate receptors on neuronal membranes within these domains. In this article the authors propose that the composition and localization of protein complexes in glutamate microdomains is abnormal in schizophrenia, leading to pathological neuroplastic changes in the structure and function of glutamate circuits in this illness.
ABSTRACT
OBJECTIVES: To determine the risk of epileptic seizures due to a brain arteriovenous malformation (AVM) or cavernous malformation (CM). METHODS: In a prospective population-based study of new diagnoses of AVMs (n = 229) or CMs (n = 139) in adults in Scotland in 1999-2003, we used annual medical records surveillance, general practitioner follow-up, and patient questionnaires to quantify the risk of seizures between clinical presentation and AVM/CM treatment, last follow-up, or death. RESULTS: The 5-year risk of first-ever seizure after presentation was higher for AVMs presenting with intracranial hemorrhage or focal neurologic deficit (ICH/FND: n = 119; 23%, 95% confidence interval [CI] 9%-37%) than for incidental AVMs (n = 40; 8%, 95% CI 0%-20%), CMs presenting with ICH/FND (n = 38; 6%, 95% CI 0%-14%), or incidental CMs (n = 57; 4%, 95% CI 0%-10%). For adults who had never experienced ICH/FND, the 5-year risk of epilepsy after first-ever seizure was higher for CMs (n = 23; 94%, 95% CI 84%-100%) than AVMs (n = 37; 58%, 95% CI 40%-76%; p = 0.02). Among adults who never experienced ICH/FND and presented with or developed epilepsy, there was no difference in the proportions achieving 2-year seizure freedom over 5 years between AVMs (n = 43; 45%, 95% CI 20%-70%) and CMs (n = 35; 47%, 95% CI 27%-67%). CONCLUSIONS: AVM-related ICH confers a significantly higher risk of a first-ever seizure compared to CMs or incidental AVMs. Adults with a CM have a high risk of epilepsy after a first-ever seizure but achieve seizure freedom as frequently as those with epilepsy due to an AVM.
Subject(s)
Epilepsy/epidemiology , Hemangioma, Cavernous, Central Nervous System/complications , Intracranial Arteriovenous Malformations/complications , Seizures/epidemiology , Adult , Epilepsy/etiology , Female , Humans , Male , Middle Aged , Odds Ratio , Prevalence , Prospective Studies , Risk , Scotland/epidemiology , Seizures/etiology , Surveys and QuestionnairesABSTRACT
OBJECTIVE: To determine the imaging and demographic characteristics of intracranial haemorrhages, which are subsequently found to be due to an underlying intracranial vascular malformation (IVM). METHODS: We compared the demographic and brain imaging characteristics of adults presenting with intracranial haemorrhage, subsequently found to be due to a brain arteriovenous malformation (BAVM), dural arteriovenous fistula (DAVF) or cavernous malformation (CM) in a prospective, population-based cohort of adults diagnosed for the first time with an IVM (The Scottish IVM Study (SIVMS)). RESULTS: Of the 141 adults in SIVMS who presented with intracranial haemorrhage, those with CMs presented at a younger age and were less handicapped. A total of 115 (82%) had intracerebral haemorrhage (ICH) with or without subarachnoid, intraventricular or subdural extension. ICH without extension into other compartments accounted for all CM bleeds, but only 50% of BAVM and DAVF bleeds. Median haematoma volumes differed (Kruskal-Wallis, p<0.0001): ICH due to BAVM (16.0 cm3, inter-quartile range (IQR) 4.7 to 42.0) and DAVF (14.1 cm3, IQR 4.9 to 21.5) were similar, but CM haematoma volumes were smaller (median 1.8 cm3, IQR 1.3 to 4.3). These findings were robust in sensitivity analyses. Small haematoma volumes occurred among all IVM types; the largest haematoma volume due to CM was 12 cm3, and volumes of >34 cm3 were only due to BAVM. CONCLUSIONS: Intracranial haemorrhages found to be due to IVMs differ in adults' age of presentation and clinical severity, as well as the volume and distribution of the haematoma within the brain compartments.
Subject(s)
Intracranial Arteriovenous Malformations/diagnosis , Population Surveillance/methods , Subarachnoid Hemorrhage/diagnosis , Adult , Aged , Arterio-Arterial Fistula/diagnosis , Diagnosis, Differential , Dura Mater/pathology , Female , Humans , Magnetic Resonance Angiography , Magnetic Resonance Imaging , Male , Middle Aged , Prospective Studies , Severity of Illness Index , Tomography, X-Ray ComputedABSTRACT
The N-methyl-d-aspartate (NMDA) subtype of glutamate receptors plays an important role in brain physiology, but excessive receptor stimulation results in seizures and excitotoxic nerve cell death. NMDA receptor-mediated neuronal excitation and injury can be prevented by high, non-physiological concentrations of the neuroinhibitory tryptophan metabolite kynurenic acid (KYNA). Here we report that endogenous KYNA, which is formed in and released from astrocytes, controls NMDA receptors in vivo. This was revealed with the aid of the dopaminergic drugs d-amphetamine and apomorphine, which cause rapid, transient decreases in striatal KYNA levels in rats. Intrastriatal injections of the excitotoxins NMDA or quinolinate (but not the non-NMDA receptor agonist kainate) at the time of maximal KYNA reduction resulted in two- to threefold increases in excitotoxic lesion size. Pre-treatment with a kynurenine 3-hydroxylase inhibitor or with dopamine receptor antagonists, i.e., two classes of pharmacological agents that prevented the reduction in brain KYNA caused by dopaminergic stimulation, abolished the potentiation of neurotoxicity. Thus, the present study identifies a previously unappreciated role of KYNA as a functional link between dopamine receptor stimulation and NMDA neurotoxicity in the striatum.
Subject(s)
Corpus Striatum/metabolism , Corpus Striatum/physiopathology , Kynurenic Acid/metabolism , Neurotoxins/metabolism , Receptors, Dopamine/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Animals , Astrocytes/metabolism , Cell Death/drug effects , Cell Death/physiology , Corpus Striatum/drug effects , Dopamine/metabolism , Dopamine Agonists/pharmacology , Excitatory Amino Acid Agonists/metabolism , Excitatory Amino Acid Agonists/toxicity , Female , Glutamic Acid/metabolism , Humans , N-Methylaspartate/metabolism , N-Methylaspartate/toxicity , Nerve Degeneration/chemically induced , Nerve Degeneration/metabolism , Nerve Degeneration/physiopathology , Neurotoxins/toxicity , Quinolinic Acid/metabolism , Quinolinic Acid/toxicity , Rats , Rats, Sprague-DawleyABSTRACT
In a subset of rats, typical antipsychotic drugs (tAPD) produce oral dyskinesias called vacuous chewing movements (VCMs) that resemble tardive dyskinesia (TD), a behavioral side effect seen in a subset of people following tAPD treatment. Morphological changes within the striatum following tAPD have been correlated to VCMs in animal models. The cholinergic system has been implicated in expression of TD. To test the hypothesis that the striatal cholinergic system is perturbed after haloperidol treatment, rats were administered haloperidol for three weeks and tested for VCMs; the striata were then processed for the immunocytochemical localization of choline-acetyltransferase (ChAT). Neuronal density measures of ChAT-labeled neurons showed a 22% decrease in haloperidol-treated versus controls rats and a 37% reduction in the lateral portion of the striatum only in rats with VCMs. These findings further support evidence of the possible involvement of the cholinergic system and the ventrolateral striatum in VCMs, and possibly TD.
Subject(s)
Antipsychotic Agents/pharmacology , Dyskinesia, Drug-Induced/physiopathology , Haloperidol/pharmacology , Interneurons/drug effects , Neostriatum/drug effects , Parasympathetic Nervous System/metabolism , Animals , Behavior, Animal/drug effects , Cell Count , Choline O-Acetyltransferase/metabolism , Dyskinesia, Drug-Induced/enzymology , Interneurons/enzymology , Neostriatum/cytology , Neostriatum/enzymology , Parasympathetic Nervous System/drug effects , Parasympathetic Nervous System/enzymology , Rats , Rats, Sprague-DawleyABSTRACT
Chronic neuroleptic treatment in rats induces vacuous chewing movements (VCMs) that mimic tardive dyskinesia. Such treatment decreases overall striatal synaptic density, but rats with VCMs also have decreased density of symmetric synapses, indicating less inhibitory synaptic transmission. This study examined the striatum to determine if enkephalinergic terminals, which form symmetric synapses, are affected. All synapses combined, asymmetric and symmetric axospinous, and enkephalinergic synapses were significantly reduced in density in the haloperidol treated group as compared to controls. A loss of asymmetric axodendritic synapses, typical of excitatory thalamic inputs, was observed preferentially in the low VCM group. A loss of symmetric axodendritic synapses was observed preferentially in the high VCM group. This study indicates that a population of synapses, other than enkephalinergic ones, is preferentially lost in the high VCM group. Moreover, lack of VCMs may be due to changes in synaptic organization that are protective as well as the absence of pathologic connections.
Subject(s)
Corpus Striatum/drug effects , Corpus Striatum/pathology , Dyskinesia, Drug-Induced/pathology , Enkephalins/metabolism , Haloperidol/toxicity , Presynaptic Terminals/drug effects , Animals , Antipsychotic Agents/toxicity , Corpus Striatum/metabolism , Dendrites/drug effects , Dendrites/pathology , Dendrites/ultrastructure , Dyskinesia, Drug-Induced/physiopathology , Immunohistochemistry , Male , Microscopy, Electron , Neural Inhibition/drug effects , Neural Inhibition/physiology , Neural Pathways/drug effects , Neural Pathways/pathology , Neural Pathways/ultrastructure , Presynaptic Terminals/pathology , Presynaptic Terminals/ultrastructure , Rats , Rats, Sprague-Dawley , Synaptic Membranes/drug effects , Synaptic Membranes/pathology , Synaptic Membranes/ultrastructure , Thalamus/drug effects , Thalamus/pathology , Thalamus/ultrastructureABSTRACT
BACKGROUND: Metabolites of the kynurenine pathway of tryptophan degradation may play a role in the pathogenesis of several human brain diseases. One of the key metabolites in this pathway, kynurenine, is either transaminated to form the glutamate receptor antagonist, kynurenate, or hydroxylated to 3-hydroxykynurenine, which in turn is further degraded to the excitotoxic N-methyl-D-aspartate receptor agonist quinolinate. Because a hypoglutamatergic tone may be involved in the pathophysiology of schizophrenia, it is conceivable that alterations in kynurenine pathway metabolism may play a role in the disease. METHODS: The tissue levels of kynurenine, kynurenate, and 3-hydroxykynurenine were measured in brain tissue specimens obtained from the Maryland Brain Collection. All three metabolites were determined in the same samples from three cortical brain regions (Brodmann areas 9, 10, and 19), obtained from 30 schizophrenic and 31 matched control subjects. RESULTS: Kynurenate levels were significantly increased in schizophrenic cases in Brodmann area 9 (2.9 +/- 2.2 vs. 1.9 +/- 1.3 pmol/mg protein, p <.05), but not in Brodmann areas 10 and 19. Kynurenine levels were elevated in schizophrenic cases in Brodmann areas 9 (35.2 +/- 28.0 vs. 22.4 +/- 14.3 pmol/mg protein; p <.05) and 19 (40.3 +/- 23.4 vs. 30.9 +/- 10.8; p <.05). No significant differences in 3-hydroxykynurenine content were observed between the two groups. In both groups, significant (p <.05) correlations were found in all three brain areas between kynurenine and kynurenate, but not between kynurenine and 3-hydroxykynurenine (p >.05). In rats, chronic (6-months) treatment with haloperidol did not cause an increase in kynurenate levels in the frontal cortex, indicating that the elevation observed in schizophrenia is not due to antipsychotic medication. CONCLUSIONS: The data demonstrate an impairment of brain kynurenine pathway metabolism in schizophrenia, resulting in elevated kynurenate levels and suggesting a possible concomitant reduction in glutamate receptor function.
Subject(s)
Frontal Lobe/chemistry , Kynurenic Acid/analysis , Kynurenine/analogs & derivatives , Kynurenine/analysis , Occipital Lobe/chemistry , Schizophrenia/metabolism , Adult , Aged , Aged, 80 and over , Animals , Antipsychotic Agents/pharmacology , Female , Haloperidol/pharmacology , Humans , Male , Middle Aged , Rats , Rats, Sprague-DawleyABSTRACT
The extracellular regulated kinases (ERK) 1 and ERK2 are members of mitogen-activated protein (MAP) kinase family that play an important role in transducing extracellular signals to the nucleus and have been implicated in a broad spectrum of biological responses. To test the hypothesis that MAP kinases may be involved in depression, we examined the activation of p44/42 MAP kinase and expression of ERK1 and ERK2 in the post-mortem brain tissue obtained from non-psychiatric control subjects (n = 11) and age- and the post-mortem interval-matched depressed suicide subjects (n = 11). We observed that p44/42 MAP kinase activity was significantly decreased in the prefrontal cortical areas (Brodmann's areas 8, 9 and 10) and the hippocampus of depressed suicide subjects without any change in the cerebellum. This decrease was associated with a decrease in mRNA and protein levels of ERK1 and ERK2. In addition, the expression of MAP kinase phosphatase (MKP)2, a 'dual function' ERK1/2 phosphatase, was increased in the prefrontal cortex and hippocampus. These studies suggest that p44/42 MAP kinases are less activated in the post-mortem brain of depressed suicide subjects and this may be because of reduced expression of ERK1/2 and increased expression of MKP2. Given the role of MAP kinases in various physiological functions and gene expression, alterations in p44/42 MAP kinase activation and expression of ERK1/2 may contribute significantly to the pathophysiology of depressive disorders.
Subject(s)
Brain/enzymology , Depression/enzymology , Gene Expression , Mitogen-Activated Protein Kinase 1/genetics , Mitogen-Activated Protein Kinases/genetics , Suicide , Adult , Aged , Cell Membrane/enzymology , Cell Nucleus/enzymology , Cytosol/enzymology , Dual-Specificity Phosphatases , Enzyme Activation , Female , Hippocampus/enzymology , Humans , Male , Middle Aged , Mitogen-Activated Protein Kinase 1/analysis , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3 , Mitogen-Activated Protein Kinase Phosphatases , Mitogen-Activated Protein Kinases/analysis , Mitogen-Activated Protein Kinases/metabolism , Phosphorylation , Prefrontal Cortex/enzymology , Protein Tyrosine Phosphatases/analysis , Protein Tyrosine Phosphatases/metabolism , RNA, Messenger/analysisABSTRACT
The developing brain is exquisitely sensitive to gonadal steroid hormones, which permanently differentiate the neural substrate during a critical developmental period. One of the more striking sexual dimorphisms in the adult rat brain is synaptic patterning in the arcuate nucleus (ARC); females have twice the number of axospinous synapses as males (Matsumoto and Arai [1980] Brain Res. 190:238-242). Previously, we have demonstrated that a similar dimorphism in spine densities on ARC dendrites is present as early as early as postnatal day 2 (PN2) in Golgi-impregnated rat brains (Mong et al. [1999] J. Neurosci. 19:1464-1472). Males have 37% fewer dendritic spines than females. Moreover, these spine densities are sensitive to changes in the hormonal milieu such that males castrated on the day of birth have a significant increase in spine density, whereas females masculinized at birth by gonadal steroid exposure have a decreased dendritic spine density. One of the limitations of the Golgi technique is the inability to confirm the presence of synapses. The current study used quantitative electron microscopy and demonstrated that testosterone exposure dramatically reduced axospinous synapses in the ARC by PN 2. Males had 54% fewer and masculinized females had 77% fewer axospinous synapses than females (P < 0.05 and P < 0.01, respectively). We previously reported that gonadal steroids induce coincident changes in neuronal and astrocyte morphology in the neonatal ARC (Mong et al., 1999), and here confirm that these changes include an altered synaptic pattern that is strikingly similar to that observed in the adult (Matsumoto and Arai, 1980).
Subject(s)
Arcuate Nucleus of Hypothalamus/drug effects , Axons/drug effects , Dendrites/drug effects , Gonadal Steroid Hormones/pharmacology , Synapses/drug effects , Testosterone/pharmacology , Animals , Animals, Newborn , Arcuate Nucleus of Hypothalamus/growth & development , Axons/physiology , Axons/ultrastructure , Dendrites/physiology , Dendrites/ultrastructure , Female , Male , Neuropil/drug effects , Neuropil/physiology , Neuropil/ultrastructure , Pregnancy , Rats , Rats, Sprague-Dawley , Sex Factors , Synapses/physiology , Synapses/ultrastructureABSTRACT
Right hemisphere damaged patients with and without left visual neglect, and age-matched controls had objects of various sizes presented within left or right body hemispace. Subjects were asked to estimate the objects' sizes or to reach out and grasp them, in order to assess visual size processing in perceptual-experiential and action-based contexts respectively. No impairments of size processing were detected in the prehension performance of the neglect patients but a generalised slowing of movement was observed, associated with an extended deceleration phase. Additionally both patient groups reached maximum grip aperture relatively later in the movement than did controls. For the estimation task it was predicted that the left visual neglect group would systematically underestimate the sizes of objects presented within left hemispace but no such abnormalities were observed. Possible reasons for this unexpected null finding are discussed.
Subject(s)
Hand Strength/physiology , Perceptual Disorders/psychology , Psychomotor Performance/physiology , Size Perception/physiology , Aged , Biomechanical Phenomena , Female , Functional Laterality/physiology , Humans , Male , Middle Aged , Neuropsychological Tests , Perceptual Disorders/etiology , Stroke/complications , Stroke/psychology , Tomography, X-Ray ComputedABSTRACT
Our previous work has shown that chronic haloperidol treatment decreases striatal symmetric synapses preferentially in rats which develop oral dyskinesias (vacuous chewing movements (VCMs)). The present experiment tests the hypothesis that olanzapine, which does not cause dyskinesia in humans or rats, would not cause the ultrastructural changes produced by haloperidol. After 6 months of treatment, VCM scores for the olanzapine group (5.1 +/- 4.5) were similar to those of controls (5.2 +/- 3.9), whereas rats in the haloperidol group were either nondyskinetic (4.3 +/- 2.2) or dyskinetic (16.9 +/- 6.7). The volume of the striatum (mm(3)), did not differ among the groups: control, 37.5 +/- 4.7; olanzapine, 36.4 +/- 4.3; haloperidol, nondyskinetic, 40.5 +/- 6.3; haloperidol, dyskinetic, 36.6 +/- 5.9. Synaptic density (per 1 microm(3)), obtained from the central region of the striatum, did not differ between the olanzapine (0.699 +/- 0.146) and control groups (0.652 +/- 0.108). The number of asymmetric synapses in the olanzapine group (0.624 +/- 0.136) was also similar to that of controls (0.550 +/- 0.090). The number of symmetric synapses in the olanzapine group (0.074 +/- 0.032) was not significantly different from that of controls (0.096 +/- 0.043). Thus, olanzapine, in contrast to haloperidol, did not produce dyskinesias or synapse loss. These results strengthen the correlation between the expression of VCMs and striatal synaptic changes and indicate that olanzapine has fewer behavioral and anatomical side effects than does haloperidol.
Subject(s)
Antipsychotic Agents/pharmacology , Neostriatum/drug effects , Pirenzepine/analogs & derivatives , Pirenzepine/pharmacology , Presynaptic Terminals/drug effects , Synapses/drug effects , Animals , Benzodiazepines , Dyskinesia, Drug-Induced/etiology , Dyskinesia, Drug-Induced/pathology , Dyskinesia, Drug-Induced/physiopathology , Haloperidol/adverse effects , Male , Neostriatum/metabolism , Neostriatum/ultrastructure , Olanzapine , Presynaptic Terminals/classification , Presynaptic Terminals/ultrastructure , Rats , Rats, Sprague-Dawley , Synapses/classification , Synapses/ultrastructureABSTRACT
OBJECTIVE: Multiple quantifiable biologic abnormalities have been localized to the hippocampus in schizophrenia. Alterations in glutamate-mediated transmission at N-methyl-D-aspartic acid (NMDA)-sensitive receptors in hippocampus have been implicated in the pathophysiology of the illness. The authors tested the hypothesis that glutamatergic transmission within and efferent from hippocampus is altered in schizophrenia. METHOD: The authors analyzed postmortem hippocampal tissue from individuals with schizophrenia and from healthy individuals. The tissue samples had been collected by two brain tissue banks, one in Maryland and the other in Melbourne, Australia. lonotropic receptor binding for the NMDA, kainate, and (3)H-amino-3-hydroxy-5-methylisoxazol-4-propionate (AMPA) receptors was quantified by using usual radioligand techniques. In situ hybridization autoradiography was used to quantify mRNA for the NMDA receptor subunits NR1, NR2A, and NR2B. RESULTS: Ligand binding to the ionotropic glutamate receptors (NMDA, kainate, and AMPA) did not differ significantly overall or in any subregion between the schizophrenia tissue and the healthy comparison tissue. The only exception was AMPA receptor binding in hippocampal subregion CA2, which was slightly but significantly less in schizophrenia. However, the level of mRNA for the NMDA receptor subunits NR1 and NR2B was significantly different between groups; in several hippocampal subregions, the level of NR1 mRNA was lower and the level of NR2B mRNA higher in schizophrenia. CONCLUSIONS: Because the NR1 subunit of the NMDA receptor is critical to full receptor activity, a reduction of NR1 in hippocampus in schizophrenia suggests a functional impairment in glutamatergic transmission at the NMDA receptor, resulting in reduced glutamatergic transmission within and possibly efferent from the hippocampus in schizophrenia. This defect could underlie a hypoglutamatergic state in regions of limbic cortex, consistent with published results from other lines of research in schizophrenia.
Subject(s)
Hippocampus/metabolism , Receptors, Glutamate/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Schizophrenia/metabolism , Adult , Animals , Antipsychotic Agents/pharmacology , Autoradiography , Female , Hippocampus/drug effects , Hippocampus/physiopathology , Humans , In Situ Hybridization , Male , Middle Aged , RNA, Messenger/analysis , Radioligand Assay , Rats , Receptors, AMPA/drug effects , Receptors, AMPA/metabolism , Receptors, AMPA/physiology , Receptors, Glutamate/drug effects , Receptors, Glutamate/physiology , Receptors, Kainic Acid/drug effects , Receptors, Kainic Acid/metabolism , Receptors, Kainic Acid/physiology , Receptors, N-Methyl-D-Aspartate/physiology , Schizophrenia/physiopathologyABSTRACT
It has been suggested that the P3 event-related potential (ERP) may mark the operation of certain working or long-term memory processes. It has also been reported that cholinergic blockade by scopolamine induces significant memory impairment and is associated with an increased latency, as well as amplitude reduction or abolition of the auditory P3, thus supporting hypothesised links between P3 and long-term memory function. An intriguing anomaly is that, while visual P3 latency is also increased by scopolamine, amplitude is not changed. The aim of this study was to make a more detailed assessment of the effects of scopolamine on the visual P3 at a drug dose known to induce memory impairment. After drug administration, memory performance was significantly impaired and visual P3 latency was significantly increased. There was little evidence of parietal P3 amplitude reduction, but frontal P3 amplitude was significantly reduced in both target and non-target conditions. These findings, when considered in the light of a more recent study of the effects of scopolamine on auditory P3, suggest that cholinergic blockade produces a common effect in both visual and auditory modalities of significant frontal P3 amplitude reduction, but no significant parietal P3 amplitude reduction. These results are consistent with the view that there are modality-independent generators of the parietal and frontal P3. The finding of drug-induced memory impairment and modulations of frontal ERP deflections is also consistent with recent evidence of a significant role for regions of the frontal lobe in encoding and retrieval of long-term memories.
Subject(s)
Evoked Potentials, Visual/drug effects , Frontal Lobe/drug effects , Mental Recall/drug effects , Muscarinic Antagonists/pharmacology , Parietal Lobe/drug effects , Scopolamine/pharmacology , Adult , Brain Mapping , Double-Blind Method , Female , Humans , Infusions, Intravenous , Male , Pattern Recognition, Visual/drug effects , Reaction Time/drug effects , Retention, Psychology/drug effectsABSTRACT
OBJECTIVE: The enzyme phosphoinositide-specific phospholipase C (PI-PLC) is a component of the phosphoinositide signal transduction system. Other components of this system have been found to be abnormal in adults and adolescents who have committed suicide, and so the authors examined whether PI-PLC activity and protein expression of PLC isozymes are abnormal in postmortem brains of teenage suicide subjects. METHOD: PI-PLC activity and protein expression of the PLC beta1, delta1, and gamma1 isozymes were examined in Brodmann's areas 8 and 9 of postmortem brains obtained from 18 teenage suicide subjects and 18 matched comparison subjects. PI-PLC activity was determined by enzymatic assay, and protein expression of the PLC isozymes was determined by the Western blot technique. RESULTS: Compared with the normal subjects, the teenage suicide subjects had significantly lower PI-PLC activity and immunolabeling of the specific PLC beta1 isozyme in both membrane and cytosol fractions of Brodmann's areas 8 and 9 combined (prefrontal cortex). There was also a significant correlation between PI-PLC activity and protein levels of the PLC beta1 isozyme in the brains of the teenage suicide subjects. There was no significant difference in PI-PLC activity or level of PLC beta1 protein between the suicide subjects with a history of mental disorders and those with no history of mental disorders; however, both groups had significantly lower PI-PLC activity and expression of PLC beta1 protein than the normal subjects. CONCLUSIONS: Low PI-PLC activity and expressed levels of the PLC beta1 isozyme in postmortem brains of suicide subjects may have clinical relevance in the pathophysiology of suicidal behavior.
Subject(s)
Isoenzymes/metabolism , Prefrontal Cortex/chemistry , Suicide/statistics & numerical data , Type C Phospholipases/metabolism , Adolescent , Adult , Child , Female , Humans , Immunoblotting , Male , Mental Disorders/epidemiology , Mental Disorders/psychology , Phosphatidylinositol Diacylglycerol-Lyase , Phosphatidylinositols/metabolism , Phosphoinositide Phospholipase C , Phospholipase C beta , Prefrontal Cortex/enzymology , Psychology, Adolescent , Racial Groups , Social BehaviorABSTRACT
Microdialysis is a widely used in vivo sampling technique commonly used to monitor extracellular levels of a variety of molecules including neurotransmitters and metabolites. To facilitate interpretation of microdialysis results, this study critically examines changes in synaptic morphology induced by microdialysis. Tissue surrounding microdialysis probes was examined using light and electron microscopy at three distances from the probe tract. Microdialysis probes were implanted into rat striatum, and after 40 h of post-operative recovery were perfused with a modified Ringer's solution. Light microscope analysis revealed tissue disruption up to 1.4 mm from the probe site. Axonal damage indicative of non-excitotoxic insult was also seen as far away from the probe as was examined. The presence of dark-degenerating neurons was also noted and estimates of neuronal densities revealed loss up to 400 microm from the probe tract. This study, the first qualitative ultrastructural investigation of neuropil surrounding the probe site, indicated swollen processes up to 1.4 mm from the probe tract. Swollen mitochondria and bloated endoplasmic reticulum suggest intracellular chemical disruption. Tissue damage resulting in synaptic and neuronal disruption may affect neurotransmitter efflux or extracellular concentrations of metabolites.