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David A Lewis

Publications and source records attributed to David A Lewis.

At least 55 records · Page 3Linked to original sources
PubMed2004

Heat shock protein 12A shows reduced expression in the prefrontal cortex of subjects with schizophrenia.

BACKGROUND: Deoxyribonucleic acid microarray analyses of dorsolateral prefrontal cortex (DLPFC) area 9 from 10 matched pairs of schizophrenic and control subjects revealed a consistent and significant decrease (p = .001; mean log2 signal difference = -.58) in transcript expression for a gene clone KIAA0417. This database entry has been recently annotated as two highly homologous members of a heat-shock protein family (HSPA12A and HSPA12B). METHODS: We followed up our initial results by in situ hybridization in subjects with schizophrenia, major depression, and a chronic haloperidol-treated nonhuman primate model. Furthermore, we investigated the distribution of HSPA12A and HSPA12B transcripts across the human and nonhuman primate brain. RESULTS: We found that HSPA12A (but not HSPA12B) is highly expressed in the human brain and shows a neuron- and region-specific transcript distribution, with strongest expression in the frontal and occipital cortical regions. HSPA12A messenger ribonucleic acid was significantly reduced (p < .01; mean log2 optical density difference = -.84) across subjects with schizophrenia but not in the DLPFC of subjects with major depression or in monkeys chronically treated with haloperidol. CONCLUSIONS: The data are consistent with metabolic alterations in schizophrenia, reflected in selective changes in the expression of certain genes encoding proteins involved in cellular metabolism or metabolic responsiveness.

Adult↗
PubMed2004

Functional properties of fast spiking interneurons and their synaptic connections with pyramidal cells in primate dorsolateral prefrontal cortex.

Recent studies suggest that fast-spiking (FS) interneurons of the monkey dorsolateral prefrontal cortex (DLPFC) exhibit task-related firing during working-memory tasks. To gain further understanding of the functional role of FS neurons in monkey DLPFC, we described the in vitro electrophysiological properties of FS interneurons and their synaptic connections with pyramidal cells in layers 2/3 of areas 9 and 46. Extracellular spike duration was found to distinguish FS cells from non-FS interneuron subtypes. However, a substantial overlap in extracellular spike duration between these populations would make classification of individual interneurons difficult. FS neurons could be divided into two main morphological groups, chandelier and basket neurons, with very similar electrophysiological properties but significantly different horizontal spread of the axonal arborization. In paired cell recordings, unitary inhibitory postsynaptic potentials (IPSPs) elicited by FS neurons in pyramidal cells had rapid time course, small amplitude at resting membrane potential, and were mediated by GABA(A) receptors. Repetitive FS neuron stimulation, partially mimicking the sustained firing of interneurons in vivo, produced short-term depression of the unitary IPSPs, present at connections made by both basket and chandelier neurons and due at least in part to presynaptic mechanisms. These results suggest that FS neurons and their synaptic connections with pyramidal cells have homogeneous physiological properties. Thus different functional roles of basket and chandelier neurons in the DLPFC in vivo must arise from the distinct properties of the interneuronal axonal arborization or from a different functional pattern of excitatory and inhibitory connections with other components of the DLPFC neuronal network.

Action Potentials↗
PubMed2004

Ultrastructural interactions between terminals expressing the norepinephrine transporter and dopamine neurons in the rat and monkey ventral tegmental area.

The norepinephrine (NE) system is implicated in the etiology and treatment of depression and drugs blocking the NE transporter (NET) are effective antidepressants. It is possible that dopamine (DA) also plays a role in depression and the action of antidepressant drugs, although the mechanisms whereby NE and DA interact have not been fully elaborated. We examined whether NE neurons might alter DA transmission via synaptic projections to cells in the ventral tegmental area (VTA) by using electron microscopic dual labeling immunocytochemistry in the rat and monkey. NET was used as a marker for NE axons, whereas the catecholamine synthetic enzyme, tyrosine hydroxylase (TH), served as a label for DA neurons. We observed three types of spatial relationships between these profiles that were similar in type but varied in frequency between rodent and primate. The most common arrangement involved nonsynaptic appositions between NET-immunoreactive (-ir) axons and TH-ir dendrites. Such relationships may facilitate extrasynaptic actions of NE on DA cell activity. The other commonly observed arrangement involved adjacent profiles that were otherwise separated by glia. These relationships may represent regions where NE is prevented from reaching DA cells. In only a few cases were synapses observed between NET-ir axons and TH-ir dendrites. This finding suggests that NE can synaptically regulate DA neurons, although functional interactions are more likely to involve extrasynaptic mechanisms. Finally, in the VTA of both species the majority of NET-ir axons exhibited no detectable TH immunoreactivity. The latter finding agrees with observations in cortical regions and represents the first report of its type in a subcortical structure.

Animals↗
PubMed2004

Pyramidal cell size reduction in schizophrenia: evidence for involvement of auditory feedforward circuits.

BACKGROUND: Subjects with schizophrenia have decreased gray matter volume of auditory cortex in structural imaging studies and exhibit deficits in auditory sensory processing that might reflect impairments of feedforward and/or feedback circuits within the auditory cortex. Recently, we reported that one component of these circuits, pyramidal cells in deep layer 3 of the auditory association cortex (area 42), has reduced mean somal volume in subjects with schizophrenia. To discriminate between involvement of feedforward and feedback circuit components, we examined pyramidal cell somal volume in layer 3 of primary auditory cortex (feedforward) and layer 5 of auditory association cortex (feedback). METHODS: We estimated somal volumes of pyramidal neurons in deep layer 3 of area 41 and layer 5 of area 42 in subjects with schizophrenia (area 41, n = 16; area 42, n = 18), each of whom was matched to one normal comparison subject for gender, age, and postmortem interval. RESULTS: In deep layer 3 of area 41, mean pyramidal cell somal volume was significantly reduced, by 10.4%. No significant reduction was present in layer 5 of area 42. CONCLUSIONS: Pyramidal cell somal volume is reduced in layer 3 of area 41 and area 42, but not in layer 5 of area 42, of subjects with schizophrenia. This pattern of abnormalities is consistent with impairments of auditory feedforward projection neurons.

Adult↗
PubMed2004

Cortical connections of the lateral mediodorsal thalamus in cynomolgus monkeys.

The prefrontal cortex has been defined as that cortical territory that has "essential or sustaining" connections with the mediodorsal (MD) nucleus of the thalamus. However, recent studies in the monkey have documented projections from MD to the more caudal, agranular regions of the frontal cortex, suggesting that the connections of MD may be characterized by a breadth of distribution and diversity of functional roles too great to be useful as a unifying and defining feature for a specific cortical territory. In this study, we placed tracer injections in the lateral divisions of MD in cynomolgus monkeys (Macaca fascicularis) to assess the relative proportions of connections devoted to diverse regions of the frontal cortex (FC). Three different patterns of label were observed in the cortex, associated with different locations within lateral MD. We have designated these as the ventrolateral MD-arcuate FC circuit, having most label in areas 8 and 6; the caudoventral MD-dorsomedial FC circuit, having most label in areas 24 and presupplementary motor area (SMA); and the anterodorsal MD-anterior FC circuit, with the most label in areas 9, 46, 12, and 10. Only two of the nine cases injected in lateral MD were predominantly connected with the anterior FC. Thus, particular locales within lateral MD are connected with multiple, functionally diverse cortical regions, including several not classically recognized as "prefrontal" areas. This divergence may distinguish MD-frontocortical and reciprocal corticothalamic pathways from the largely segregated pathways arising from the other thalamic nuclei that are interconnected with the frontal cortex, such as those from the ventrolateral nuclear group.

Animals↗
PubMed2004

Stereological analysis of the mediodorsal thalamic nucleus in schizophrenia: volume, neuron number, and cell types.

The mediodorsal thalamic nucleus (MD) is the principal relay nucleus for the prefrontal cortex, a brain region thought to be dysfunctional in schizophrenia. Several, but not all, postmortem studies of the MD in schizophrenia have reported decreased volume and total neuronal number. However, it is not clear whether the findings are specific for schizophrenia nor is it known which subtypes of thalamic neurons are affected. We studied the left MD in 11 subjects with schizophrenia, 9 control subjects, and 12 subjects with mood disorders. Based on morphological criteria, we divided the neurons into two subclasses, presumably corresponding to projection neurons and local circuit neurons. We estimated MD volume and the neuron number of each subclass using methods based on modern unbiased stereological principles. We also estimated the somal volumes of each subclass using a robust, but biased, approach. In addition, we investigated the left MD in four cynomolgus monkeys chronically exposed to haloperidol and in four control monkeys in order to assess the possible effects of antipsychotic medications. The three human subject groups did not differ in any of the measures. In addition, no differences were observed between the two groups of monkeys. Thus, these findings do not support the hypothesis that the MD is a locus of pathology in schizophrenia, although they cannot rule out important functional or structural changes in parameters not measured. Like other studies, this investigation is subject to the limitations involved in sampling from a heterogeneous population emphasizing the need to continue to improve the application of robust, unbiased techniques to quantitative studies of this complex brain disorder.

Adult↗
PubMed2004

Synaptic efficacy during repetitive activation of excitatory inputs in primate dorsolateral prefrontal cortex.

Neurons in the monkey dorsolateral prefrontal cortex (DLPFC) fire persistently during the delay period of working memory tasks. To determine how repetitive firing affects the efficacy of synaptic inputs to DLPFC layer 3 neurons, we examined the effects of repetitive presynaptic stimulation on the amplitude and temporal summation of EPSPs. Recordings were obtained in monkey DLPFC brain slices from regular spiking (RS) pyramidal cells and two types of interneurons, fast spiking (FS) and adapting non-pyramidal (ANP) cells. Repetitive stimulation of presynaptic axons in layer 3 caused EPSP depression in RS and FS neurons, but EPSP facilitation in ANP cells. A shorter EPSP duration produced weaker temporal summation in FS neurons compared to the other cell classes. Thus, due to the combined effects of dynamic changes in EPSP amplitude and differences in temporal summation, the effect of a presynaptic spike train differed according to the postsynaptic cell class. Similar results were obtained when recording unitary EPSPs evoked in connected pairs of presynaptic RS pyramidal cells and postsynaptic RS, FS or ANP neurons. In addition, similar differences in the efficacy of sustained inputs among cell classes were observed when delay-related firing was reproduced in vitro by stimulating inputs with the timing of spike trains recorded from the DLPFC of monkeys performing a delayed-response task. We suggest that the transition from baseline firing rates to higher frequency delay-related firing may lead to the differential activation of distinct cell populations, with corresponding significant effects on the patterns of activity in local prefrontal circuits.

Action Potentials↗
PubMed2004

Neuropathologic correlates of late-onset major depression.

Late life major depression (LLMD) is frequently associated with cognitive impairment, and increases the risk for subsequent dementia. Cerebrovascular disease, Alzheimer's disease (AD), and dementia with Lewy bodies (DLB) have all been hypothesized to contribute to this increased risk, though prospective studies have yet to examine these hypotheses with autopsy confirmation of the clinical diagnoses. The aim of this study is to examine the rates of cerebrovascular, AD, and DLB pathology among the first 10 participants in an LLMD brain tissue donation program. Subjects' psychiatric diagnoses and cognitive status were prospectively determined during their participation in clinical research protocols of the Intervention Research Center for Late Life Mood Disorders. After death, final clinical diagnoses were made using all clinical information, while blind to neuropathologic diagnoses. Neuropathologic assessments were conducted blind to final clinical diagnoses. Rates of neuropathology were compared with those in a cohort of subjects with dementia, without a history of LLMD, participating in an Alzheimer Disease Research Center. Seven (70%) subjects had evidence of onset of a dementia prior to death. LLMD with dementia was significantly associated with a neuropathologic diagnosis of AD. Cerebrovascular disease and DLB pathology were also frequent in the LLMD subjects with dementia, and were found in an LLMD subject without dementia. Rates of AD, DLB, and cerebrovascular disease were similar to those in the comparison subjects. These preliminary findings suggest that AD is the predominant neuropathologic condition in LLMD subjects with dementia. Further assessment of the role of comorbid cerebrovascular disease and comorbid DLB is needed.

Adult↗
PubMed2004

Serotonin1A receptors at the axon initial segment of prefrontal pyramidal neurons in schizophrenia.

OBJECTIVE: Inhibition mediated by gamma-aminobutyric acid at the axon initial segment of pyramidal neurons appears to be altered in the prefrontal cortex in schizophrenia. This study examined the densities and laminar distribution of axon initial segments labeled with an antibody against the serotonin(1A) (5-HT(1A)) receptor, which also mediates inhibitory regulation of pyramidal neurons, in subjects with schizophrenia. METHOD: The densities and laminar distribution of axon initial segments with 5-HT(1A)-like immunoreactivity were assessed in postmortem tissue from the prefrontal cortex (Brodmann's area 46) of 14 matched triads of subjects with schizophrenia, subjects with major depressive disorder, and comparison subjects with no psychiatric disorder. RESULTS: The relative densities of the labeled axon initial segment in both the superficial and the deep cortical layers did not differ across the three subject groups. CONCLUSIONS: The findings do not support a role for altered serotonin transmission by means of the 5-HT(1A) receptor in dysfunction of prefrontal cortex pyramidal neurons in schizophrenia.

Axons↗
PubMed2004

Postnatal development of prefrontal inhibitory circuits and the pathophysiology of cognitive dysfunction in schizophrenia.

The typical appearance of the clinical features of schizophrenia during late adolescence or early adulthood suggests that adolescence-related neurodevelopmental events may contribute to the pathophysiology of this disorder. Here the role that GABA-mediated inhibition in the dorsal lateral prefrontal cortex (DLPFC) plays in regulating working memory, a core cognitive process that matures late and that is disturbed in schizophrenia, is reviewed. Recent studies are summarized that demonstrate (1) that certain pre- and postsynaptic markers of GABA neurotransmission in the monkey DLPFC exhibit striking changes during adolescence, and (2) that these same markers are markedly altered in the DLPFC of subjects with schizophrenia. The implications of these findings for treatment and prevention strategies are discussed.

Adolescent↗
PubMed2003

Selective alterations in prefrontal cortical GABA neurotransmission in schizophrenia: a novel target for the treatment of working memory dysfunction.

RATIONALE: Disturbances in critical cognitive processes, such as working memory, are now regarded as core features of schizophrenia, but available pharmacological treatments produce little or no improvement in these cognitive deficits. Although other explanations are possible, these cognitive deficits appear to reflect a disturbance in executive control, the processes that facilitate complex information processing and behavior and that include context representation and maintenance, functions dependent on the dorsolateral prefrontal cortex (DLPFC). Studies in non-human primates indicate that normal working memory function depends upon appropriate GABA neurotransmission in the DLPFC, and alterations in markers of GABA neurotransmission are well documented in the DLPFC of subjects with schizophrenia. OBJECTIVES: Thus, the purpose of this paper is to review the nature of the altered GABA neurotransmission in the DLPFC in schizophrenia, and to consider how these findings might inform the search for new treatments for cognitive dysfunction in this illness. RESULTS AND CONCLUSIONS: Postmortem studies suggest that markers of reduced GABA neurotransmission in schizophrenia may be selective for, or at least particularly prominent in, the subclass of GABA neurons, chandelier cells, that provide inhibitory input to the axon initial segment of populations of pyramidal neurons. Given the critical role that chandelier cells play in synchronizing the activity of pyramidal neurons, the pharmacological amelioration of this deficit may be particularly effective in normalizing the neural network activity required for working memory function. Because GABA(A) receptors containing the a(2) subunit are selectively localized to the axon initial segment of pyramidal cells, and appear to be markedly up-regulated in schizophrenia, treatment with novel benzodiazepine-like agents with selective activity at GABA(A) receptors containing the a(2) subunit may be effective adjuvant agents for improving working memory function in schizophrenia.

Animals↗
PubMed2003

Postnatal development of pre- and postsynaptic GABA markers at chandelier cell connections with pyramidal neurons in monkey prefrontal cortex.

The protracted postnatal maturation of the primate prefrontal cortex (PFC) is associated with substantial changes in the number of excitatory synapses on pyramidal neurons, whereas the total number of inhibitory synapses appears to remain constant. In this study, we sought to determine whether the developmental changes in excitatory input to pyramidal cells are paralleled by changes in functional markers of inhibitory inputs to pyramidal neurons. The chandelier subclass of gamma-aminobutyric acid (GABA) neurons provides potent inhibitory control over pyramidal neurons by virtue of their axon terminals, which form distinct vertical structures (termed cartridges) that synapse at the axon initial segment (AIS) of pyramidal neurons. Thus, we examined the relative densities, laminar distributions, and lengths of presynaptic chandelier axon cartridges immunoreactive for the GABA membrane transporter 1 (GAT1) or the calcium-binding protein parvalbumin (PV) and of postsynaptic pyramidal neuron AIS immunoreactive for the GABA(A) receptor alpha(2) subunit (GABA(A) alpha(2)) in PFC area 46 of 38 rhesus monkeys (Macaca mulatta). From birth through 2 years of age, the relative densities and laminar distributions of these three markers exhibited different trajectories, suggesting developmental shifts in the weighting of at least some factors that determine inhibition at the AIS. In contrast, from 2 to 4 years of age, all three markers exhibited similar declines in density and length that paralleled the periadolescent pruning of excitatory synapses to pyramidal neurons. Across development, the predominant laminar location of PV-labeled cartridges and GABA(A) alpha(2)-immunoreactive AIS shifted from the middle to superficial layers, whereas the laminar distribution of GAT1-positive cartridges did not change. Together, these findings suggest that the maturation of inhibitory inputs to the AIS of PFC pyramidal neurons is a complex process that may differentially affect the firing patterns of subpopulations of pyramidal neurons at specific postnatal time points.

Animals↗
PubMed2003

Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia.

Markers of inhibitory neurotransmission are altered in the prefrontal cortex (PFC) of subjects with schizophrenia, and several lines of evidence suggest that these alterations may be most prominent in the subset of GABA-containing neurons that express the calcium-binding protein, parvalbumin (PV). To test this hypothesis, we evaluated the expression of mRNAs for PV, another calcium-binding protein, calretinin (CR), and glutamic acid decarboxylase (GAD67) in postmortem brain specimens from 15 pairs of subjects with schizophrenia and matched control subjects using single- and dual-label in situ hybridization. Signal intensity for PV mRNA expression in PFC area 9 was significantly decreased in the subjects with schizophrenia, predominantly in layers III and IV. Analysis at the cellular level revealed that this decrease was attributable principally to a reduction in PV mRNA expression per neuron rather than by a decreased density of PV mRNA-positive neurons. In contrast, the same measures of CR mRNA expression were not altered in schizophrenia. These findings were confirmed by findings from cDNA microarray studies using different probes. Across the subjects with schizophrenia, the decrease in neuronal PV mRNA expression was highly associated (r = 0.84) with the decrease in the density of neurons containing detectable levels of GAD67 mRNA. Furthermore, simultaneous detection of PV and GAD67 mRNAs revealed that in subjects with schizophrenia only 55% of PV mRNA-positive neurons had detectable levels of GAD67 mRNA. Given the critical role that PV-containing GABA neurons appear to play in regulating the cognitive functions mediated by the PFC, the selective alterations in gene expression in these neurons may contribute to the cognitive deficits characteristic of schizophrenia.

Adult↗
PubMed2003

Somal size of prefrontal cortical pyramidal neurons in schizophrenia: differential effects across neuronal subpopulations.

BACKGROUND: Cognitive dysfunction in schizophrenia may be related to morphologic abnormalities of pyramidal neurons in the dorsal prefrontal cortex (dPFC) and the largest pyramidal neurons in deep layer 3 may be most affected. Immunoreactivity (IR) for the nonphosphorylated epitopes of neurofilament protein (NNFP) identifies a subset of large dPFC deep layer 3 pyramidal neurons. We tested the hypotheses that the average size of NNFP-IR neurons is smaller in schizophrenia and that the decrease in size of these neurons is greater than that observed in the general population of deep layer 3 pyramidal neurons. METHODS: We estimated the mean somal volume of NNFP-IR neurons in deep layer 3 of 9 in 13 matched pairs of control and schizophrenia subjects and compared the differences in somal size of NNFP-IR neurons to the differences in size of all deep layer 3 pyramidal neurons identified in Nissl-stained material. RESULTS: In subjects with schizophrenia, the somal volume of NNFP-IR neurons was nonsignificantly decreased by 6.6%, whereas that of the Nissl-stained pyramidal neurons was significantly decreased by 14.2%. CONCLUSIONS: These results suggest that the NNFP-IR subpopulation of dPFC pyramidal neurons are not preferentially affected in schizophrenia. Thus, a subpopulation of dPFC deep layer 3 pyramidal neurons, other than those identified by NNFP-IR, may be selectively vulnerable in schizophrenia.

Adult↗