Synaptic alterations in pyramidal cells following genetic manipulation of neuronal excitability in monkey prefrontal cortex.

The dorsolateral prefrontal cortex (DLPFC) plays a crucial role in primate cognition, integrating multimodal information to generate top-down signals for cognitive control. During cognitive tasks, the DLPFC displays activity patterns of exceptional complexity and duration not observed in other cortical areas or species. These activity patterns are likely associated with the unique physiological and morphological properties of primate DLPFC pyramidal neurons (PNs).

Synaptic alterations in pyramidal cells following genetic manipulation of neuronal excitability in monkey prefrontal cortex.

Unlabelled: In schizophrenia, layer 3 pyramidal neurons (L3PNs) in the dorsolateral prefrontal cortex (DLPFC) are thought to receive fewer excitatory synaptic inputs and to have lower expression levels of activity-dependent genes and of genes involved in mitochondrial energy production. In concert, these findings from previous studies suggest that DLPFC L3PNs are hypoactive in schizophrenia, disrupting the patterns of activity that are crucial for working memory, which is impaired in the illness. However, whether lower PN activity produces alterations in inhibitory and/or excitatory synaptic strength has not been tested in the primate DLPFC.

Differential gene expression between callosal and ipsilateral projection neurons in the monkey dorsolateral prefrontal and posterior parietal cortices.

Reciprocal connections between primate dorsolateral prefrontal (DLPFC) and posterior parietal (PPC) cortices, furnished by subsets of layer 3 pyramidal neurons (PNs), contribute to cognitive processes including working memory (WM). A different subset of layer 3 PNs in each region projects to the homotopic region of the contralateral hemisphere. These ipsilateral (IP) and callosal (CP) projections, respectively, appear to be essential for the maintenance and transfer of information during WM.

Differential gene expression in layer 3 pyramidal neurons across 3 regions of the human cortical visual spatial working memory network.

Visual spatial working memory (vsWM) is mediated by a distributed cortical network composed of multiple nodes, including primary visual (V1), posterior parietal (PPC), and dorsolateral prefrontal (DLPFC) cortices. Feedforward and feedback information is transferred among these nodes via projections furnished by pyramidal neurons (PNs) located primarily in cortical layer 3. Morphological and electrophysiological differences among layer 3 PNs across these nodes have been reported; however, the transcriptional signatures underlying these differences have not been examined in the human brain.

Mapping Phosphodiesterase 4D (PDE4D) in Macaque Dorsolateral Prefrontal Cortex: Postsynaptic Compartmentalization in Layer III Pyramidal Cell Circuits.

cAMP signaling has powerful, negative effects on cognitive functions of the primate dorsolateral prefrontal cortex (dlPFC), opening potassium channels to reduce firing and impair working memory, and increasing tau phosphorylation in aging neurons. This contrasts with cAMP actions in classic circuits, where it enhances plasticity and transmitter release. PDE4 isozymes regulate cAMP actions, and thus have been a focus of research and drug discovery.

GluN2D-mediated excitatory drive onto medial prefrontal cortical PV+ fast-spiking inhibitory interneurons.

Deficits in fast-spiking inhibitory interneurons (FSINs) within the dorsolateral prefrontal cortex (dlPFC) are hypothesized to underlie cognitive impairment associated with schizophrenia. Though representing a minority of interneurons, this key cell type coordinates broad neural network gamma-frequency oscillations, associated with cognition and cognitive flexibility. Here we report expression of GluN2D mRNA selectively in parvalbumin positive cells of human postmortem dlPFC tissue, but not pyramidal neurons, with little to no GluN2C expression in either cell type.

Distinct Properties of Layer 3 Pyramidal Neurons from Prefrontal and Parietal Areas of the Monkey Neocortex.

In primates, working memory function depends on activity in a distributed network of cortical areas that display different patterns of delay task-related activity. These differences are correlated with, and might depend on, distinctive properties of the neurons located in each area. For example, layer 3 pyramidal neurons (L3PNs) differ significantly between primary visual and dorsolateral prefrontal (DLPFC) cortices.

Laser capture microdissection-targeted mass spectrometry: a method for multiplexed protein quantification within individual layers of the cerebral cortex.

The mammalian neocortex is organized into layers distinguished by the size, packing density, and connectivity of their constituent neurons. Many neuropsychiatric illnesses are complex trait disorders with etiologic factors converging on neuronal protein networks. Cortical pathology of neuropsychiatric diseases, such as schizophrenia, is often restricted to, or more pronounced in, certain cortical layers, suggesting that genetic vulnerabilities manifest with laminar specificity.

Transcriptome Alterations in Prefrontal Pyramidal Cells Distinguish Schizophrenia From Bipolar and Major Depressive Disorders.

Background: Impairments in certain cognitive processes (e.g., working memory) are typically most pronounced in schizophrenia (SZ), intermediate in bipolar disorder, and least in major depressive disorder.

Altered Expression of ARP2/3 Complex Signaling Pathway Genes in Prefrontal Layer 3 Pyramidal Cells in Schizophrenia.

Objective: Lower dendritic spine density on layer 3 pyramidal cells in the dorsolateral prefrontal cortex (DLPFC) appears to contribute to cognitive dysfunction in schizophrenia, whereas psychosis is associated with excessive dopamine release in the striatum. These findings may be related via excitatory projections from the DLPFC to the ventral mesencephalon, the location of dopamine cells projecting to the striatum. Consistent with this hypothesis, deletion of the actin-related protein-2/3 (ARP2/3) complex, which regulates the actin cytoskeleton supporting dendritic spines, produced spine loss in cortical pyramidal cells and striatal hyperdopaminergia in mice.

Reciprocal Alterations in Regulator of G Protein Signaling 4 and microRNA16 in Schizophrenia.

N-methyl-d-aspartate receptor (NMDAR) hypofunction in the dorsolateral prefrontal cortex (DLPFC) has been implicated in the pathology of schizophrenia. NMDAR activity is negatively regulated by some G protein-coupled receptors (GPCRs). Signaling through these GPCRs is reduced by Regulator of G protein Signaling 4 (RGS4).

Dysregulated ErbB4 Splicing in Schizophrenia: Selective Effects on Parvalbumin Expression.

Objective: Alternative splicing of ErbB4 transcripts is dysregulated in the dorsolateral prefrontal cortex in schizophrenia. ErbB4 regulates the activity of parvalbumin interneurons, and therefore dysregulated ErbB4 splicing could contribute to lower parvalbumin interneuron activity and consequently lower parvalbumin levels in schizophrenia. However, ErbB4 is also present in calretinin interneurons, which are not affected in schizophrenia.

Altered expression of CDC42 signaling pathway components in cortical layer 3 pyramidal cells in schizophrenia.

Background: Cognitive dysfunction in schizophrenia is associated with a lower density of dendritic spines on deep layer 3 pyramidal cells in the dorsolateral prefrontal cortex (DLPFC). These alterations appear to reflect dysregulation of the actin cytoskeleton required for spine formation and maintenance. Consistent with this idea, altered expression of genes in the cell division cycle 42 (CDC42)-CDC42 effector protein (CDC42EP) signaling pathway, a key organizer of the actin cytoskeleton, was previously reported in DLPFC gray matter from subjects with schizophrenia.

Developmental Expression Patterns of GABAA Receptor Subunits in Layer 3 and 5 Pyramidal Cells of Monkey Prefrontal Cortex.

Cortical pyramidal neuron activity is regulated in part through inhibitory inputs mediated by GABAA receptors. The subunit composition of these receptors confers distinct functional properties. Thus, developmental shifts in subunit expression will likely influence the characteristics of pyramidal cell firing and the functional maturation of processes that depend on these neurons.

Lower gene expression for KCNS3 potassium channel subunit in parvalbumin-containing neurons in the prefrontal cortex in schizophrenia.

Objective: In schizophrenia, alterations in markers of cortical GABA neurotransmission are prominent in parvalbumin-containing neurons. Parvalbumin neurons selectively express KCNS3, the gene encoding the Kv9.3 potassium channel α-subunit.

Perisomatic inhibition and cortical circuit dysfunction in schizophrenia.

Deficits of cognitive control in schizophrenia are associated with altered gamma oscillations in the prefrontal cortex. Paralbumin basket interneurons, which innervate the perisomatic region of pyramidal neurons, appear to play a key role in generating cortical gamma oscillations. In the prefrontal cortex of subjects with schizophrenia, alterations are present in both pre- and post-synaptic markers of the strength of GABA inputs from parvalbumin basket neurons to pyramidal neurons.

Cortical deficits of glutamic acid decarboxylase 67 expression in schizophrenia: clinical, protein, and cell type-specific features.

Objective: Cognitive deficits in schizophrenia are associated with altered activity of the dorsolateral prefrontal cortex, which has been attributed to lower expression of the 67 kDa isoform of glutamic acid decarboxylase (GAD67), the major γ-aminobutyric acid (GABA)-synthesizing enzyme. However, little is known about the relationship of prefrontal GAD67 mRNA levels and illness severity, translation of the transcript into protein, and protein levels in axon terminals, the key site of GABA production and function.

Method: Quantitative polymerase chain reaction was used to measure GAD67 mRNA levels in postmortem specimens of dorsolateral prefrontal cortex from subjects with schizophrenia and matched comparison subjects with no known history of psychiatric or neurological disorders (N=42 pairs).

Altered expression of regulators of the cortical chloride transporters NKCC1 and KCC2 in schizophrenia.

Context: Disturbances in markers of cortical γ-aminobutyric acid neurotransmission are a common finding in schizophrenia. The nature of γ-aminobutyric acid neurotransmission (hyperpolarizing or depolarizing) depends on the local intracellular chloride concentration. In the central nervous system, the intracellular chloride level is determined by the activity of 2 cation-chloride transporters, NKCC1 and KCC2.

Infragranular gene expression disturbances in the prefrontal cortex in schizophrenia: signature of altered neural development?

The development of the human neocortex gives rise to a complex cytoarchitecture, grouping together cells with similar structure, connectivity and function. As a result, the six neocortical laminae show distinct molecular content. In schizophrenia, many anatomical and neurochemical changes appear to be restricted to a subset of lamina and/or cell types.

Protracted developmental trajectories of GABAA receptor alpha1 and alpha2 subunit expression in primate prefrontal cortex.

Background: In schizophrenia, working memory dysfunction is associated with altered expression of gamma-aminobutyric acid (GABA)(A) receptor alpha1 and alpha2 subunits in the dorsolateral prefrontal cortex (DLPFC). In rodents, cortical alpha subunit expression shifts from low alpha1 and high alpha2 to high alpha1 and low alpha2 during early postnatal development. Because these two alpha subunits confer different functional properties to the GABA(A) receptors containing them, we determined whether this shift in alpha1 and alpha2 subunit expression continues through adolescence in the primate DLPFC, potentially contributing to the maturation of working memory during this developmental period.

Molecular evidence for increased expression of genes related to immune and chaperone function in the prefrontal cortex in schizophrenia.

Background: Schizophrenia is characterized by complex gene expression changes. The transcriptome alterations in the prefrontal cortex have been the subject of several recent postmortem studies that yielded both convergent and divergent findings.

Methods: To increase measurement precision, we used a custom-designed DNA microarray platform with long oligonucleotides and multiple probes with replicates.

Molecular markers distinguishing supragranular and infragranular layers in the human prefrontal cortex.

The human neocortex is organized into six layers that are differentiated by the size and packing density of their constituent neurons. The gene products that guide the establishment of this lamination have been studied extensively, but the gene expression gradients present across the layers of the adult human neocortex are mostly unknown. As the supragranular (SG) and infragranular (IG) layers of the human prefrontal cortex (PFC) differ in their connectivity and developmental time course, we hypothesized that the SG and IG layers will show distinct differences in their transcriptomes.

Correlation of transcriptome profile with electrical activity in temporal lobe epilepsy.

The biology underlying epileptic brain activity in humans is not well understood and likely depends on changes in gene expression. We performed a microarray transcriptome profiling of 12 anterolateral temporal cortical samples originating from five individuals who suffered with temporal lobe epilepsy for at least 10 years. Prior to partial lobectomy, intraoperative electrocorticography was performed on the cortical surface of each patient.

The 3'-azido group is not the primary determinant of 3'-azido-3'-deoxythymidine (AZT) responsible for the excision phenotype of AZT-resistant HIV-1.

The mechanism of human immunodeficiency virus (HIV) 1 resistance to 3'-azido-3'-deoxythymidine (AZT) involves reverse transcriptase (RT)-catalyzed phosphorolytic excision of the chain-terminating AZT-5'-monophosphate (AZTMP). Primers terminated with AZTMP are generally better substrates for this reaction than those terminated with 2',3'-dideoxynucleoside-5'-monophosphate (2',3'-ddNMP) analogs that lack a 3'-azido moiety. This led to the hypothesis that the 3'-azido group is a major structural determinant for maintaining the primer terminus in the appropriate site for phosphorolytic excision of AZTMP by AZT-resistant (AZT(R)) RT.