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PubMed2003

[3H]RX 821002 in human dorsolateral prefrontal cortex: no changes in postmortem tissue from subjects with schizophrenia.

One of the major differences between the atypical antipsychotic drugs clozapine and olanzapine is that clozapine has a two-fold higher affinity for the alpha(2)-adrenoreceptors. As clozapine can have therapeutic benefits in individuals that do not respond to other antipsychotic drugs, this raises the possibility that changes in the alpha(2)-adrenoreceptors could be a marker for a predisposition to treatment resistance. A methodology has been optimised to measure the binding of [3H]RX 821002 to alpha(2)-adrenoreceptors in human postmortem CNS and has shown that these receptors are not altered in Brodmann's area 9 from subjects with schizophrenia. These data add to those of one other study that showed the alpha(2)-adrenoreceptors were not altered in Brodmann's area 10 and the hippocampus from subjects with schizophrenia, and do not support the hypothesis that changes in alpha(2)-adrenoreceptors are a marker for treatment resistance in schizophrenia.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed1999

Phospholipase pathway in Alzheimer's disease brains: decrease in Galphai in dorsolateral prefrontal cortex.

There is substantial evidence that G-protein-associated signaling pathways in the brain are altered in Alzheimer's disease (AD). Using quantitative immunoblotting we find a significant decrease in Galphai levels in every AD case examined compared to controls (mean Galphai level in AD was 43.5+/-7.4% of control). Galphao levels were slightly decreased, but Galphaq and betagamma were normal. Phospholipase C-beta1, but not gamma1, levels were also decreased. Total phospholipase C activity and ceramide levels were not changed. Thus, in AD, there is impairment in the Galphai-associated signaling pathway in neurons.

Aged↗
PubMed2001

Dorsolateral prefrontal cortex activation during automatic auditory duration-mismatch processing in humans: a positron emission tomography study.

This study aimed to identify the neural networks underlying automatic and active auditory deviant detection in six healthy subjects using positron emission tomography. Eight alternating blocks of standard and standard plus duration-deviant tones were presented while subjects performed a visual discrimination task. In an additional four blocks, the subjects then performed an auditory discrimination task on the deviant tones. Actively attending the deviant tones increased regional cerebral blood flow (rCBF) in the superior temporal and inferior frontal gyrus as well as in the superior and medio-frontal gyrus. When performing the visual task and presented with deviant tones, significant increase of rCBF was detected in the caudate nucleus, cerebellum, posterior cingulate, inferior frontal and pre-central gyrus thus indicating automatic extra-pyramidal processing of auditory duration deviants.

Acoustic Stimulation↗
PubMed2000

Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia revisited.

Evidence implicates subtle neuronal pathology of the prefrontal cortex (PFC) in schizophrenia, but how this pathology is reflected in physiological neuroimaging experiments remains controversial. We investigated PFC function in schizophrenia using functional magnetic resonance imaging (fMRI) and a parametric version of the n-back working memory (WM) task. In a group of patients who performed relatively well on this task, there were three fundamental deviations from the 'healthy' pattern of PFC fMRI activation to varying WM difficulty. The first characteristic was a greater magnitude of PFC fMRI activation in the context of slightly impaired WM performance (i.e. physiological inefficiency). The second was that the significant correlations between behavioral WM performance and dorsal PFC fMRI activation were in opposite directions in the two groups. Third, the magnitude of the abnormal dorsal PFC fMRI response was predicted by an assay of N-acetylaspartate concentrations (NAA) in dorsal PFC, a measure of neuronal pathology obtained using proton magnetic resonance spectroscopy. Patients had significantly lower dorsal PFC NAA than controls and dorsal PFC NAA inversely predicted the fMRI response in dorsal PFC (areas 9, 46) to varying WM difficulty - supporting the assumption that abnormal PFC responses arose from abnormal PFC neurons. These data suggest that under certain conditions the physiological ramifications of dorsal PFC neuronal pathology in schizophrenia includes exaggerated and inefficient cortical activity, especially of dorsal PFC.

Adolescent↗
PubMed2002

Reduced neuronal size and glial cell density in area 9 of the dorsolateral prefrontal cortex in subjects with major depressive disorder.

Reductions in glial cell density and neuronal size have been described recently in major depressive disorder (MDD). Considering the important trophic influence of glia on neurons, we hypothesized that this glial cell deficit is more prominent close to neurons. In this investigation we have characterized neuronal and glia cytoarchitecture in prefrontal area 9 using spatial point pattern techniques and two-dimensional measures of cell size and density. In post-mortem brain tissue of subjects with MDD, schizophrenia, bipolar disorder (BPD), and normal controls (15 subjects per group), we examined the laminar location and size of all neurons and glial nuclei in a 500 microm wide strip of cortex extending from the pia to the grey-white matter border. In MDD, we observed reductions in glial cell density (30%; P = 0.007) in layer 5 and neuronal size (20%; P = 0.003) in layer 6. We also found that glial cell density (34%; P = 0.003) was reduced in layer 5 in schizophrenia, while neuronal size was reduced in layers 5 (14%) (P = 0.006) and 6 (18%; P = 0.007) in BPD. The spatial pattern investigation of neurons and glia demonstrated no alteration in the clustering of glia about neurons between control and patient groups. These findings confirm that glial cell loss and neuronal size reductions occur in the deeper cortical layers in MDD, but provide no support for the hypothesis that an altered spatial distribution of glia about neurons plays a role in the development of these changes.

Analysis of Variance↗
PubMedDate not supplied

Cellular and subcellular sites for noradrenergic action in the monkey dorsolateral prefrontal cortex as revealed by the immunocytochemical localization of noradrenergic receptors and axons.

A series of electron microscopic immunocytochemical studies was performed to analyze subcellular sites for noradrenergic modulation in monkey prefrontal cortex. One out of 12 noradrenergic varicosities, identified by dopamine beta-hydroxylase immunocytochemistry within single ultrathin sections, forms morphologically identifiable junctions with small dendrites and spines. Accordingly, alpha2-adrenergic receptors, almost all of which are of the A-subtype, that occur in spines are localized discretely over postsynaptic membranes. alpha2-Adrenergic receptors are also found at sites along axons, dendritic shafts and astrocytic processes lacking morphologically identifiable synaptic junctions, suggesting that these receptors are activated by volume transmission. In particular, axonal alpha2-adrenergic receptors occur mostly at pre-terminal regions, suggesting that axo-axonic interactions may mediate reduction of neurotransmitter release at sites other than axo-spinous junctions by closing voltage-dependent calcium channels. These results indicate that noradrenergic modulation of prefrontal cortex involves synaptic interactions at spines of pyramidal neurons and nonsynaptic volume transmission to glia, dendritic shafts and axons.

Animals↗
PubMed2004

Localization of calcium-binding proteins in physiologically and morphologically characterized interneurons of monkey dorsolateral prefrontal cortex.

In the primate neocortex, little is known about the possible associations between functional subclasses of GABA neurons, their morphological properties and calcium-binding protein (CaBP) content. We used whole-cell current clamp recordings, combined with intracellular labeling and fluorescence immunohistochemistry, to determine these relationships for interneurons in layers 2-3 of monkey prefrontal cortex (PFC). Eighty-one interneurons were included in the analysis. Thirty-eight of these cells showed immunoreactivity for one of the three CaBPs tested. Co-localization of more than one CaBP was not observed in any of the interneurons examined. Interneurons with different CaBPs formed distinct populations with specific physiological membrane properties and morphological features. Parvalbumin (PV)-positive cells had the physiological properties characteristic of fast-spiking interneurons (FS) and the morphology of basket or chandelier neurons. Most calretinin (CR)-containing cells had the physiological properties ascribed to non-fast-spiking cells (non-FS) and a vertically oriented axonal morphology, similar to that of double bouquet cells. Calbindin (CB)-positive interneurons also had non-FS properties and included cells with double bouquet morphology or with a characteristic dense web of axonal collaterals in layer 1. Classification of the interneurons based on cluster analysis of multiple electrophysiological properties suggested the existence of at least two distinct groups of interneurons. The first group contained mainly PV-positive FS cells and the second group consisted predominantly of CR- and CB-positive non-FS interneurons. These findings may help to illuminate the functional roles of different groups of interneurons in primate PFC circuitry.

Action Potentials↗
PubMed2006

Increased levels of SNAP-25 and synaptophysin in the dorsolateral prefrontal cortex in bipolar I disorder.

OBJECTIVE: In order to identify whether the mechanisms associated with neurotransmitter release are involved in the pathologies of bipolar disorder and schizophrenia, levels of presynaptic [synaptosomal-associated protein-25 (SNAP-25), syntaxin, synaptophysin, vesicle-associated membrane protein, dynamin I] and structural (neuronal cell adhesion molecule and alpha-synuclein) neuronal markers were measured in Brodmann's area 9 obtained postmortem from eight subjects with bipolar I disorder (BPDI), 20 with schizophrenia and 20 controls. METHODS: Determinations of protein levels were carried out using Western blot techniques with specific antibodies. Levels of mRNA were measured using real-time polymerase chain reaction. RESULTS: In BPDI, levels of SNAP-25 (p < 0.01) and synaptophysin (p < 0.05) increased. There were no changes in schizophrenia or any other changes in BPDI. Levels of mRNA for SNAP-25 were decreased in BPDI (p < 0.05). CONCLUSION: Changes in SNAP-25 and synaptophysin in BPDI suggest that changes in specific neuronal functions could be linked to the pathology of the disorder.

Antibodies↗
PubMed1989

Mnemonic coding of visual space in the monkey's dorsolateral prefrontal cortex.

1. An oculomotor delayed-response task was used to examine the spatial memory functions of neurons in primate prefrontal cortex. Monkeys were trained to fixate a central spot during a brief presentation (0.5 s) of a peripheral cue and throughout a subsequent delay period (1-6 s), and then, upon the extinction of the fixation target, to make a saccadic eye movement to where the cue had been presented. Cues were usually presented in one of eight different locations separated by 45 degrees. This task thus requires monkeys to direct their gaze to the location of a remembered visual cue, controls the retinal coordinates of the visual cues, controls the monkey's oculomotor behavior during the delay period, and also allows precise measurement of the timing and direction of the relevant behavioral responses. 2. Recordings were obtained from 288 neurons in the prefrontal cortex within and surrounding the principal sulcus (PS) while monkeys performed this task. An additional 31 neurons in the frontal eye fields (FEF) region within and near the anterior bank of the arcuate sulcus were also studied. 3. Of the 288 PS neurons, 170 exhibited task-related activity during at least one phase of this task and, of these, 87 showed significant excitation or inhibition of activity during the delay period relative to activity during the intertrial interval. 4. Delay period activity was classified as directional for 79% of these 87 neurons in that significant responses only occurred following cues located over a certain range of visual field directions and were weak or absent for other cue directions. The remaining 21% were omnidirectional, i.e., showed comparable delay period activity for all visual field locations tested. Directional preferences, or lack thereof, were maintained across different delay intervals (1-6 s). 5. For 50 of the 87 PS neurons, activity during the delay period was significantly elevated above the neuron's spontaneous rate for at least one cue location; for the remaining 37 neurons only inhibitory delay period activity was seen. Nearly all (92%) neurons with excitatory delay period activity were directional and few (8%) were omnidirectional. Most (62%) neurons with purely inhibitory delay period activity were directional, but a substantial minority (38%) was omnidirectional. 6. Fifteen of the neurons with excitatory directional delay period activity also had significant inhibitory delay period activity for other cue directions. These inhibitory responses were usually strongest for, or centered about, cue directions roughly opposite those optimal for excitatory responses.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Neuronal activity related to saccadic eye movements in the monkey's dorsolateral prefrontal cortex.

1. Single-neuron activity was recorded from the prefrontal cortex of monkeys performing saccadic eye movements in oculomotor delayed-response (ODR) and visually guided saccade (VGS) tasks. In the ODR task the monkey was required to maintain fixation of a central spot throughout the 0.5-s cue and 3.0-s delay before making a saccadic eye movement in the dark to one of four or eight locations where the visual cue had been presented. The same locations were used for targets in the VGS tasks; however, unlike the ODR task, saccades in the VGS tasks were visually guided. 2. Among 434 neurons recorded from prefrontal cortex within and surrounding the principal sulcus (PS), 147 changed their discharge rates in relation to saccadic eye movements in the ODR task. Their response latencies relative to saccade initiation were distributed between -192 and 460-ms, with 22% exhibiting presaccadic activity and 78% exhibiting only postsaccadic activity. Among PS neurons with presaccadic activity, 53% also had postsaccadic activity when the monkey made saccadic eye movements opposite to the directions for which the presaccadic activity was observed. 3. Almost all (97%) PS neurons with presaccadic activity were directionally selective. The best direction and tuning specificity of each neuron were estimated from parameters used to fit a Gaussian tuning curve function. The best direction for 62% of the neurons with presaccadic activity was toward the contralateral visual field, with the remaining neurons having best directions toward the ipsilateral field (23%) or along the vertical meridian (15%). 4. Most postsaccadic activity of PS neurons (92%) was also directionally selective. The best direction for 48% of these neurons was toward the contralateral visual field, with the remaining neurons having best directions toward the ipsilateral field (36%) or along the vertical meridian (16%). Eighteen percent of the neurons with postsaccadic activity showed a reciprocal response pattern: excitatory responses occurred for one set of saccade directions, whereas inhibitory responses occurred for roughly the opposite set of directions. 5. Sixty PS neurons with saccade-related activity in the ODR task were also examined in a VGS task. Forty of these neurons showed highly similar profiles of directional specificity and response magnitude in both tasks, 13 showed saccade-related activity only in the ODR task, and 7 changed their response characteristics between the ODR and VGS tasks.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗