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Articles by D. A. Lewis
Total Records ( 3 ) for D. A. Lewis
  E Sibille , Y Wang , J Joeyen Waldorf , C Gaiteri , A Surget , S Oh , C Belzung , G. C Tseng and D. A. Lewis

OBJECTIVE: Major depressive disorder is a heterogeneous illness with a mostly uncharacterized pathology. Recent gene array attempts to identify the molecular underpinnings of the illness in human postmortem subjects have not yielded a consensus. The authors hypothesized that controlling several sources of clinical and technical variability and supporting their analysis with array results from a parallel study in the unpredictable chronic mild stress (UCMS) rodent model of depression would facilitate identification of the molecular pathology of major depression. METHOD: Large-scale gene expression was monitored in postmortem tissue from the anterior cingulate cortex and amygdala in paired male subjects with familial major depression and matched control subjects without major depression (N=14–16 pairs). Area dissections and analytical approaches were optimized. Results from the major depression group were compared with those from the UCMS study and confirmed by quantitative polymerase chain reaction and Western blot. Gene coexpression network analysis was performed on transcripts with conserved major depression-UCMS effects. RESULTS: Significant and bidirectional predictions of altered gene expression were identified in amygdala between major depression and the UCMS model of depression. These effects were detected at the group level and also identified a subgroup of depressed subjects with a more homogeneous molecular pathology. This phylogenetically conserved "molecular signature" of major depression was reversed by antidepressants in mice, identified two distinct oligodendrocyte and neuronal phenotypes, and participated in highly cohesive and interactive gene coexpression networks. CONCLUSIONS: These studies demonstrate that the biological liability to major depression is reflected in a persistent molecular pathology that affects the amygdala, and support the hypothesis of maladaptive changes in this brain region as a putative primary pathology in major depression.

  D. W Volk , S. M Eggan and D. A. Lewis

Certain cognitive deficits in individuals with schizophrenia have been linked to disturbed gamma-aminobutyric acid (GABA) and glutamate neurotrans-mission in the prefrontal cortex. Thus, it is important to understand how the mechanisms that regulate GABA and glutamate neurotransmission are altered in schizophrenia. For example, group I metabo-tropic glutamate receptors (mGluR1, mGluR5) modulate both GABA and gluta-mate systems. In addition, regulator of G protein signaling 4 (RGS4) reduces intra-cellular signaling through several different G protein-coupled receptors, including group I mGluRs. Finally, the endocannabinoid system plays an important role in regulating GABA and glutamate neurotrans-mission. The status of endocannabinoid ligands, such as 2-arachidonoylglycerol, can be inferred in part through measures of diacylglycerol lipase and monoglyceride lipase, which synthesize and degrade 2-arachidonoylglycerol, respectively.


Quantitative polymerase chain reaction was used to measure mRNA levels for group I mGluRs, RGS4, and markers of the endocannabinoid system in the prefrontal cortex Brodmann's area 9 of 42 schizophrenia subjects and matched normal comparison subjects. Similar analyses in monkeys chronically exposed to haloperidol, olanzapine, or placebo were also conducted.


Schizophrenia subjects had higher mRNA levels for mGluR1 and lower mRNA levels for RGS4, and these differences did not appear to be attributable to antipsychotic medications or other potential confounds. In contrast, no differences between subject groups were found in mRNA levels for endocannabinoid synthesizing and metabolizing enzymes.


Together, higher mGluR1 and lower RGS4 mRNA levels may represent a disturbed "molecular hub" in schizophrenia that may disrupt the function of prefrontal cortical networks, including both GABA and glutamate systems.

  A. V Zaitsev , N. V Povysheva , G Gonzalez Burgos , D Rotaru , K. N Fish , L. S Krimer and D. A. Lewis

The heterogeneity of -aminobutyric acid interneurons in the rodent neocortex is well-established, but their classification into distinct subtypes remains a matter of debate. The classification of interneurons in the primate neocortex is further complicated by a less extensive database of the features of these neurons and by reported interspecies differences. Consequently, in this study we characterized 8 different morphological types of interneurons from monkey prefrontal cortex, 4 of which have not been previously classified. These interneuron types differed in their expression of molecular markers and clustered into 3 different electrophysiological classes. The first class consisted of fast-spiking parvalbumin-positive chandelier and linear arbor cells. The second class comprised 5 different morphological types of continuous-adapting calretinin- or calbindin-positive interneurons that had the lowest level of firing threshold. However, 2 of these morphological types had short spike duration, which is not typical for rodent adapting cells. Neurogliaform cells (NGFCs), which coexpressed calbindin and neuropeptide Y, formed the third class, characterized by strong initial adaptation. They did not exhibit the delayed spikes seen in rodent NGFCs. These results indicate that primate interneurons have some specific properties; consequently, direct translation of classification schemes developed from studies in rodents to primates might be inappropriate.

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