Functional architecture of the prefrontal cortex

The architecture of the primate prefrontal cortex (PFC), including its connections with other brain regions, appears to be specialized to mediate complex cognitive processes such as those that depend upon working memory. The normal organization of PFC neural circuitry and the underlying patterns of gene expression that subserve these functions are examined through a complementary set of research approaches utilizing the macaque monkey as a model system for the human brain. Recent findings include the following: 1) Different subclasses of GABA interneurons play distinct roles in cortical activity. We found that the axon terminals of three different cell types differ in the relative levels of proteins that regulate GABA neurotransmission, providing a potential molecular basis for differences in interneuron function. 2) We have characterized distinct classes of pyramidal neurons in the monkey PFC, following on our earlier work of a classification scheme for interneurons based on their anatomical, biochemical and electrophysiological features. 3) We have defined the nature of inhibitory regulation of GABA neurons in monkey PFC. 4) Pre-synaptic effects of NMDA receptors enhance inhibition of pyramidal cells by parvalbumin GABA neurons, suggesting a novel mechanism for involvement of NMDA receptors in schizophrenia. 5) Layer 3 pyramidal neurons, essential for working memory, differ between the PFC,  posterior parietal and primary visual cortices in monkeys and humans. These findings may contribute to functional differences between these regions during working memory tasks. 6) The relative proportions of subtypes of GABA neurons, and their expression levels of specific gene products, differ between PFC and primary visual cortex, providing a basis for the different functional roles of these two regions in working memory.

Fish KN, Sweet RA, Lewis DA: Differential distribution of proteins regulating GABA synthesis and reuptake in axon boutons of subpopulations of cortical interneurons. Cereb Cortex 21:2450-2460, 2011. PMCID: PMC3183419

Zaitsev A, Povysheva N, Gonzalez-Burgos G, Lewis DA: Electrophysiological classes of layers 2/3 pyramidal cells in monkey prefrontal cortex. J Neurophysiol 108:595-609, 2012. PMCID: PMC3404790

Rotaru DC, Olezene C, Miyamae T, Povysheva NV, Zaitsev AV, Lewis DA, Gonzalez-Burgos G: Functional properties of GABA synaptic inputs onto GABA neurons in monkey prefrontal cortex. J Neurophysiol 113:1850-1861, 2015. PMCID: PMC4359991

Pafundo DE, Miyamae T, Lewis DA, Gonzalez-Burgos G: Presynaptic effects of N-Methyl-D-Aspartate receptors enhance parvalbumin cell-mediated inhibition of pyramidal cells in mouse prefrontal cortex. Biol Psychiatry 84:460-470, 2018. PMCID: PMC6068001

Gonzalez-Burgos G, Miyamae T, Krimer Y, Gulchina Y, Pafundo DE, Krimer O, Bazmi H, Arion D, Enwright JF, Fish K, Lewis DA: Distinct properties of layer 3 pyramidal neurons from prefrontal and parietal areas of the monkey neocortex. J Neurosci 39(37):7277-7290, 2019. PMCID: PMC6759021

Dienel SJ, Ciesielski AJ, Bazmi HH, Profozich EA, Fish KN, Lewis DA. Distinct laminar and cellular patterns of GABA neuron transcript expression in monkey prefrontal and visual cortices. Cereb Cortex 31:2345-2363, 2021. PMCID: PMC8023857​

Enwright Iii JF, Arion D, MacDonald WA, Elbakri R, Pan Y, Vyas G, Berndt A, Lewis DA. Differential gene expression in layer 3 pyramidal neurons across 3 regions of the human cortical visual spatial working memory network. Cereb Cortex. 2022 Feb 1:bhac009. doi: 10.1093/cercor/bhac009. [Epub ahead of print] PubMed PMID: 35106549

Development of PFC circuitry and function

The cognitive process mediated by the PFC undergo a protracted course of postnatal maturation extending through adolescence, the developmental periods that appear to be critical for the manifestation of the clinical syndrome of schizophrenia. Consequently, our research strategy involves characterizing the postnatal development of monkey PFC circuitry. Special emphasis is placed on the maturational events, such as synaptogenesis and synaptic pruning, which occur during early postnatal life and adolescence, respectively. Recent findings include the following: 1) Multi-label confocal microscopy revealed that the boutons of parvalbumin-containing chandelier neurons undergo a different developmental trajectory than the boutons of parvalbumin-containing basket cells, suggesting cell-type specific mechanisms of maturation of those GABAergic neurons. 2) Using pools of individually-dissected pyramidal neurons from PFC layers 3 and 5, we found that the expression of GABA-A receptor subunits in these neurons exhibit postnatal trajectories through adolescence that differ in a subunit- and cell type-specific fashion, resulting in complex changes in the kinetics of GABA neurotransmission across development. 3) Across postnatal development in the monkey PFC, perisomatic inhibitory inputs to pyramidal cells increase in strength and speed, consistent with an increasing influence over the generation of gamma oscillations. 4) Developmental pruning of excitatory inputs to parvalbumin neurons is driven by cell type-specific shifts in splicing of ErbB. 5) The timing of these shifts in expression suggests that early, rather than later, postnatal development may be a vulnerable period for layer 3 pyramidal neurons. Disruption of the normal developmental trajectories of these transcripts may contribute to layer 3 pyramidal neuron spine deficits in individuals who are later diagnosed with schizophrenia. 6) Markers of glutamate and GABA neurotransmission exhibit distinct patterns of development across regions of the cortical visual-spatial working memory network in monkeys.

Fish KN, Hoftman G, Sheikh W, Kitchens M, Lewis DA: Parvalbumin-containing chandelier and basket cell boutons have distinctive modes of maturation in monkey prefrontal cortex. J Neurosci 33:8352-8358, 2013. PMCID: PMC3684962

Datta D, Arion D, Lewis DA: Developmental expression patterns of GABAA receptor subunits in layer 3 and 5 pyramidal cells of monkey prefrontal cortex. Cereb Cortex 25:2295-2305, 2015. PMCID: PMC4494034

Gonzalez Burgos G, Miyamae T, Pafundo DE, Yoshino H, Rotaru DC, Hoftman G, Datta D, Zhang Y, Hammond M, Sampson AR, Fish KN, Ermentrout GB, Lewis DA: Functional maturation of GABA synapses during postnatal development of the monkey dorsolateral prefrontal cortex. Cereb Cortex 25:4076-93, 2015. PMCID: PMC4626828

Chung W, Wills ZP, Fish KN, Lewis DA: Developmental pruning of excitatory synaptic inputs to parvalbumin interneurons in monkey prefrontal cortex. Proc Natl Acad Sci USA 114:E629-E637, 2017. PMCID: PMC5278439

Dienel S, Bazmi H, Lewis DA. Development of transcripts regulating dendritic spines in layer 3 pyramidal cells of the monkey prefrontal cortex: Implications for the pathogenesis of schizophrenia. Neurobiol Dis. 105:132-141, 2017. PMCID: PMC5542021

Hoftman GD, Bazmi HH, Ciesielski AJ, Dinka LA, Chen K, Lewis DA. Postnatal development of glutamate and GABA transcript expression in monkey visual, parietal, and prefrontal cortices. Cereb Cortex: 31:2026-2037, 2021. PMCID: PMC8248841​

Molecular circuitry alterations in schizophrenia

Utilizing the results of our studies in monkeys, we generate and test hypotheses regarding the elements of PFC circuitry that might be dysfunctional in schizophrenia and related disorders. These hypotheses are then tested in postmortem human brain specimens from subjects with schizophrenia, normal comparison subjects, and subjects with mood disorders. Recent findings include the following: 1) Using a multi-label confocal light microscopic approach, parvalbumin-containing GABAergic axonal boutons from basket cells were identified and synaptic inputs of these boutons were defined based on their appositions to GABAA receptor α 1 subunit clusters. The density of parvalbumin basket cells inputs was unchanged in the PFC of subjects with schizophrenia, but levels of GAD67 and PV proteins were lower in these axon terminals. These findings suggest that parvalbumin basket cell dysfunction in schizophrenia reflects molecular and not structural changes in these neurons and their axon terminals. 2) Neuronal pentraxin 2 (NARP) is secreted from pyramidal cells and regulates excitatory synapses on parvalbumin neurons. NARP expression is lower in layer 3 pyramidal neurons in schizophrenia and is associated with the predicted downregulation of the activity-dependent expression of GAD67 mRNA in the illness. 3) Pyramidal neurons and parvalbumin interneurons in PFC layers 3 and 5 from subjects with schizophrenia exhibit distinctive gene expression profiles consistent with a hypometabolic state, which may be due to 4) deficits in dendritic spines resulting from impaired expression of genes regulating actin dynamics. 5) In contrast, subjects with bipolar or major depressive disorder exhibit few gene expression changes in PFC pyramidal neurons. 6) Molecular alterations in markers of excitatory and inhibitory neurotransmission in layer 3 show distinct patterns across cortical regions in the distributed network mediating working memory. 7) Alterations in ErbB4 splicing may mediate parvalbumin disturbances across psychiatric diagnoses. 8) Schizophrenia and bipolar disorder do not share similar mitochondrial alterations in the PFC; the selective and coordinated down-regulation of energy production genes in schizophrenia is consistent with the effects of chronic reductions in pyramidal neuron firing.

Glausier JR, Fish KN, Lewis DA: Altered parvalbumin basket cell inputs in the dorsolateral prefrontal cortex of schizophrenia subjects. Mol Psychiatry 19:30-36, 2014. PMCID: PMC3874728

Kimoto S, Zaki MM, Bazmi HH, Lewis DA: Altered markers of cortical γ-aminobutyric acid neuronal activity in schizophrenia: Role of the NARP gene. JAMA Psychiatry 72:747-756, 2015. PMCID: PMC4734385

Arion D, Corradi J, Tang S, Datta D, Boothe F, He A, Cacace A, Zaczek R, Albright C, Tseng G, Lewis DA. Distinctive transcriptome alterations of prefrontal pyramidal neurons in schizophrenia and schizoaffective disorder. Mol Psychiatry 20:1397-1405, 2015. PMCID: PMC4492919

Datta D, Arion D, Roman KM, Volk DW, Lewis DA: Altered expression of ARP2/3 complex signaling pathway genes in prefrontal layer 3 pyramidal cells in schizophrenia. Am J Psychiatry 174:163-171, 2017. PMCID: PMC5288270

Arion D, Huo Z, Enwright JF, Corradi JP, Tseng G, Lewis DA. Transcriptome alterations in prefrontal pyramidal cells distinguish schizophrenia from bipolar and major depressive disorders. Biol Psychiatry 82:594-600, 2017. PMCID: PMC5610065

Enwright JF, Huo Z, Arion D, Corradi JP, Tseng G, Lewis DA. Transcriptome alterations of prefrontal cortical parvalbumin neurons in schizophrenia. Mol Psychiatry 23:1606–1613, 2018. PMCID: PMC5938166

Hoftman G, Dienel S, Bazmi H, Zhang Y, Chen, K, Lewis DA. Altered gradients of glutamate and GABA transcripts in the cortical visuospatial working memory network in schizophrenia. Biol Psychiatry 83:670-679, 2018. PMCID: PMC5862743

Chung DW, Chung Y, Bazmi HH, Lewis DA. Altered ErbB4 splicing and cortical parvalbumin interneuron dysfunction in schizophrenia and mood disorders. Neuropsychopharmacology 43:2478–2486, 2018. PMCID: PMC6180093

Glausier JR, Datta D, Fish KN, Chung DW, Melchitzky DS, Lewis DA. Laminar differences in the targeting of dendritic spines by cortical pyramidal neurons and interneurons in human dorsolateral prefrontal cortex. Am J Psychiatry: 177:1140-1150, 2020. PubMed PMID: 33212224

Kimoto S, Hashimoto T, Berry KJ, Tsubomoto M, Yamaguchi Y, Enwright JF, Chen K, Kawabata R, Kikuchi M, Kishimoto T, Lewis DA. Expression of actin- and oxidative phosphorylation-related transcripts across the cortical visuospatial working memory network in unaffected comparison and schizophrenia subjects. Neuropsychopharmacology. 2022 Jan 15. doi: 10.1038/s41386-022-01274-9. [Epub ahead of print] PMID: 35034100

Pathogenesis of schizophrenia: Role of cannabinoids

Understanding the potential pathogenic significance of any brain alteration associated with schizophrenia requires the determination of whether the observed abnormality represents a potential casual factor, a deleterious consequence of more primary events, a compensatory response, or a confound of a co-occurring factor such as psychotropic drug use. Distinguishing among these alternatives requires “proof of principle” approaches that involve experimental manipulations in rodent or primate model systems. Recent findings regarding the role of the endocannabinoid system in schizophrenia include the following: 1) Levels of the cannabinoid 1 receptor (CB1R) mRNA and protein are lower in the PFC of schizophrenia subjects, but levels of ligand binding to receptor are higher. The combination of lower levels of CB1R mRNA and protein with higher CB1R receptor binding may reflect either altered trafficking of the receptor resulting in higher levels of membrane-bound CB1R or higher CB1R affinity. In either case, greater CB1R receptor availability may contribute to the increased susceptibility of schizophrenia subjects to the deleterious effects of cannabis use. 2) Reduced levels of the enzyme that produces GABA (GAD67) can induce lower mRNA levels of the cannabinoid 1 receptor (CB1R), supporting the hypothesis that lower cortical levels of CB1R mRNA in schizophrenia may partially compensate for deficient GABA synthesis by reducing endocannabinoid suppression of GABA release. 3) Repeated exposure of adolescent monkeys to THC, the active ingredient in cannabis, can produce impairments in working memory similar to those seen in schizophrenia. 4) Continued training can overcome the adverse effects of THC on learning working memory tasks.

Eggan SM, Hashimoto T, Lewis DA: Reduced cortical cannabinoid 1 receptor messenger RNA and protein expression in schizophrenia. Arch Gen Psychiatry 65:772-784, 2008. PMCID: PMC2890225

Eggan SM, Lazarus MS, Stoyak SR, Volk DW, Glausier JR, Huang J, Lewis DA: Cortical GAD67 deficiency results in lower cannabinoid 1 receptor mRNA expression: Implications for schizophrenia. Biol Psychiatry 71:114-119, 2012. PMCID: PMC3237751

Verrico CD, Gu H, Peterson M, Sampson AR, Lewis DA: Repeated Δ9-tetrahydrocannabinol exposure in adolescent monkeys: Persistent effects selective for spatial working memory. Am J Psychiatry 171:416-425, 2014. PMCID: PMC4012614

Verrico CD, Mathai DS, Gu H, Sampson AR, Lewis DA: Recovery from impaired working memory performance during chronic Δ-9-tetrahydrocannabinol administration to adolescent rhesus monkeys. J Psychopharmacol 34(2):211-220, 2020. PMCID: PMC8173701​

Pathophysiology and treatment of schizophrenia

Research in the Lewis Lab is designed to define the pathophysiological processes that give rise to the cognitive deficits of schizophrenia, with the ultimate goal of identifying and validating potential targets for novel therapeutic interventions. Examples of such findings include the following: 1) In healthy comparison subjects, the tissue distribution volume (VT) of [11C] flumazenil, a benzodiazepine-specific PET tracer, is significantly increased across all cortical brain regions after administration of a GABA membrane transporter blocker.  In contrast, subjects with schizophrenia show no increase. The lack of effect was most prominent in an antipsychotic-naïve group.  Furthermore, in the healthy comparison group, but not the schizophrenia group, [11C]flumazenil VT is positively correlated with gamma-band oscillation power, demonstrating for the first time an in vivo impairment in GABA transmission in schizophrenia. 2) Alterations in GABA neurotransmission in schizophrenia can reduce the strength of inhibitory connections in a cell type-specific manner and contribute to impaired neural synchrony and cognitive deficits, suggesting that interventions aimed at augmenting the efficacy of GABA neurotransmission might be of therapeutic value. 3) A preliminary study indicates that enhanced GABA activity at α2 subunit-containing GABAA receptors improves behavioral and electrophysiological measures of prefrontal function in subjects with schizophrenia.

Lewis DA, Cho RY, Carter CS, Eklund K, Forster S, Kelly MA, Montrose D: Subunit-selective modulation of GABA type A receptor neurotransmission and cognition in schizophrenia. Am J Psychiatry 165:1585-1593, 2008. PMCID: PMC2876339

Frankle WG, Cho RY, Prasad KM, Mason NS, Paris J, Himes ML, Walker C, Lewis DA, Narendran R: In vivo measurement of GABA transmission in healthy subjects and schizophrenia patients. Am J Psychiatry 172:1148-1159, 2015. PMCID: PMC5070491

Gonzalez-Burgos G, Cho RY, Lewis DA: Alterations in cortical network oscillations and parvalbumin neurons in schizophrenia. Biol Psychiatry 77:1031-1040, 2015. PMCID: PMC4444373

Laboratory of David A. Lewis, MD

Researching the neural circuitry of the prefrontal cortex and related brain regions, and the alterations of this circuitry in schizophrenia.



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UPMC Western Psychiatric Hospital
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University of Pittsburgh
Department of Psychiatry
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