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.

Muscarinic M1 Receptors Modulate Working Memory Performance and Activity via KCNQ Potassium Channels in the Primate Prefrontal Cortex.

Working memory relies on the dorsolateral prefrontal cortex (dlPFC), where microcircuits of pyramidal neurons enable persistent firing in the absence of sensory input, maintaining information through recurrent excitation. This activity relies on acetylcholine, although the molecular mechanisms for this dependence are not thoroughly understood. This study investigated the role of muscarinic M1 receptors (M1Rs) in the dlPFC using iontophoresis coupled with single-unit recordings from aging monkeys with naturally occurring cholinergic depletion.

Role of KCNQ potassium channels in stress-induced deficit of working memory.

The prefrontal cortex (PFC) mediates higher cognition but is impaired by stress exposure when high levels of catecholamines activate calcium-cAMP-protein kinase A (PKA) signaling. The current study examined whether stress and increased cAMP-PKA signaling in rat medial PFC (mPFC) reduce pyramidal cell firing and impair working memory by activating KCNQ potassium channels. KCNQ2 channels were found in mPFC layers II/III and V pyramidal cells, and patch-clamp recordings demonstrated KCNQ currents that were increased by forskolin or by chronic stress exposure, and which were associated with reduced neuronal firing.

The 7q11.23 Protein DNAJC30 Interacts with ATP Synthase and Links Mitochondria to Brain Development.

Despite the known causality of copy-number variations (CNVs) to human neurodevelopmental disorders, the mechanisms behind each gene's contribution to the constellation of neural phenotypes remain elusive. Here, we investigated the 7q11.23 CNV, whose hemideletion causes Williams syndrome (WS), and uncovered that mitochondrial dysfunction participates in WS pathogenesis.

Core Differences in Synaptic Signaling Between Primary Visual and Dorsolateral Prefrontal Cortex.

Neurons in primary visual cortex (V1) are more resilient than those in dorsolateral prefrontal cortex (dlPFC) in aging, schizophrenia and Alzheimer's disease. The current study compared glutamate and neuromodulatory actions in macaque V1 to those in dlPFC, and found striking regional differences. V1 neuronal firing to visual stimuli depended on AMPA receptors, with subtle NMDA receptor contributions, while dlPFC depends primarily on NMDA receptors.

The aged rhesus macaque manifests Braak stage III/IV Alzheimer's-like pathology.

Introduction: An animal model of late-onset Alzheimer's disease is needed to research what causes degeneration in the absence of dominant genetic insults and why the association cortex is particularly vulnerable to degeneration.

Methods: We studied the progression of tau and amyloid cortical pathology in the aging rhesus macaque using immunoelectron microscopy and biochemical assays.

Results: Aging macaques exhibited the same qualitative pattern and sequence of tau and amyloid cortical pathology as humans, reaching Braak stage III/IV.

mGluR2 versus mGluR3 Metabotropic Glutamate Receptors in Primate Dorsolateral Prefrontal Cortex: Postsynaptic mGluR3 Strengthen Working Memory Networks.

The newly evolved circuits in layer III of primate dorsolateral prefrontal cortex (dlPFC) generate the neural representations that subserve working memory. These circuits are weakened by increased cAMP-K+ channel signaling, and are a focus of pathology in schizophrenia, aging, and Alzheimer's disease. Cognitive deficits in these disorders are increasingly associated with insults to mGluR3 metabotropic glutamate receptors, while reductions in mGluR2 appear protective.

Ultrastructural evidence for impaired mitochondrial fission in the aged rhesus monkey dorsolateral prefrontal cortex.

Dorsolateral prefrontal cortex mediates high-order cognitive functions that are impaired early in the aging process in monkeys and humans. Here, we report pronounced changes in mitochondrial morphology in dendrites of dorsolateral prefrontal cortex neurons from aged rhesus macaques. Electron microscopy paired with 3D reconstruction from serial sections revealed an age-related increase in mitochondria with thin segments that intermingled with enlarged ones, the 'mitochondria-on-a-string' phenotype, similar to those recently reported in patients with Alzheimer's disease.

Dopamine's Actions in Primate Prefrontal Cortex: Challenges for Treating Cognitive Disorders.

The prefrontal cortex (PFC) elaborates and differentiates in primates, and there is a corresponding elaboration in cortical dopamine (DA). DA cells that fire to both aversive and rewarding stimuli likely project to the dorsolateral PFC (dlPFC), signaling a salient event. Since 1979, we have known that DA has an essential influence on dlPFC working memory functions.

Stress Impairs Prefrontal Cortical Function via D1 Dopamine Receptor Interactions With Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels.

Background: Psychiatric disorders such as schizophrenia are worsened by stress, and working memory deficits are often a central feature of illness. Working memory is mediated by the persistent firing of prefrontal cortical (PFC) pyramidal neurons. Stress impairs working memory via high levels of dopamine D1 receptor (D1R) activation of cyclic adenosine monophosphate signaling, which reduces PFC neuronal firing.

cAMP-PKA phosphorylation of tau confers risk for degeneration in aging association cortex.

The pattern of neurodegeneration in Alzheimer's disease (AD) is very distinctive: neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau selectively affect pyramidal neurons of the aging association cortex that interconnect extensively through glutamate synapses on dendritic spines. In contrast, primary sensory cortices have few NFTs, even in late-stage disease. Understanding this selective vulnerability, and why advancing age is such a high risk factor for the degenerative process, may help to reveal disease etiology and provide targets for intervention.

Nicotinic α7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex.

The cognitive function of the highly evolved dorsolateral prefrontal cortex (dlPFC) is greatly influenced by arousal state, and is gravely afflicted in disorders such as schizophrenia, where there are genetic insults in α7 nicotinic acetylcholine receptors (α7-nAChRs). A recent behavioral study indicates that ACh depletion from dlPFC markedly impairs working memory [Croxson PL, Kyriazis DA, Baxter MG (2011) Nat Neurosci 14(12):1510-1512]; however, little is known about how α7-nAChRs influence dlPFC cognitive circuits. Goldman-Rakic [Goldman-Rakic (1995) Neuron 14(3):477-485] discovered the circuit basis for working memory, whereby dlPFC pyramidal cells excite each other through glutamatergic NMDA receptor synapses to generate persistent network firing in the absence of sensory stimulation.

Neuromodulation of thought: flexibilities and vulnerabilities in prefrontal cortical network synapses.

This review describes unique neuromodulatory influences on working memory prefrontal cortical (PFC) circuits that coordinate cognitive strength with arousal state. Working memory arises from recurrent excitation within layer III PFC pyramidal cell NMDA circuits, which are afflicted in aging and schizophrenia. Neuromodulators rapidly and flexibly alter the efficacy of these synaptic connections, while leaving the synaptic architecture unchanged, a process called dynamic network connectivity (DNC).

Constellation of HCN channels and cAMP regulating proteins in dendritic spines of the primate prefrontal cortex: potential substrate for working memory deficits in schizophrenia.

Schizophrenia associates with impaired prefrontal cortical (PFC) function and alterations in cyclic AMP (cAMP) signaling pathways. These include genetic insults to disrupted-in-schizophrenia (DISC1) and phosphodiesterases (PDE4s) regulating cAMP hydrolysis, and increased dopamine D1 receptor (D1R) expression that elevates cAMP. We used immunoelectron microscopy to localize DISC1, PDE4A, PDE4B, and D1R in monkey PFC and to view spatial interactions with hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that gate network inputs when opened by cAMP.

Therapeutic implications for striatal-enriched protein tyrosine phosphatase (STEP) in neuropsychiatric disorders.

Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific phosphatase that modulates key signaling molecules involved in synaptic plasticity and neuronal function. Targets include extracellular-regulated kinase 1 and 2 (ERK1/2), stress-activated protein kinase p38 (p38), the Src family tyrosine kinase Fyn, N-methyl-D-aspartate receptors (NMDARs), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). STEP-mediated dephosphorylation of ERK1/2, p38, and Fyn leads to inactivation of these enzymes, whereas STEP-mediated dephosphorylation of surface NMDARs and AMPARs promotes their endocytosis.

Dynamic Network Connectivity: A new form of neuroplasticity.

Prefrontal cortical (PFC) working memory functions depend on pyramidal cell networks that interconnect on dendritic spines. Recent research has revealed that the strength of PFC network connections can be rapidly and reversibly increased or decreased by molecular signaling events within slender, elongated spines: a process we term Dynamic Network Connectivity (DNC). This newly discovered form of neuroplasticity provides great flexibility in mental state, but also confers vulnerability and limits mental capacity.

Mapping the regulator of G protein signaling 4 (RGS4): presynaptic and postsynaptic substrates for neuroregulation in prefrontal cortex.

Regulator of G protein signaling 4 (RGS4) regulates intracellular signaling via G proteins and is markedly reduced in the prefrontal cortex (PFC) of patients with schizophrenia. Characterizing the expression of RGS4 within individual neuronal compartments is thus key to understanding its actions on individual G protein-coupled receptors (GPCRs). Here we present an ultrastructural reference map of RGS4 protein in macaque PFC based on immunogold electron microscopic analysis.

Major vault protein is expressed along the nucleus-neurite axis and associates with mRNAs in cortical neurons.

Major Vault Protein (MVP), the main constituent of the vault ribonucleoprotein particle, is highly conserved in eukaryotic cells and upregulated in a variety of tumors. Vaults have been speculated to function as cargo transporters in several cell lines, yet no work to date has characterized the protein in neurons. Here we first describe the cellular and subcellular expression of MVP in primate and rodent cerebral cortex, and in cortical neurons in vitro.

Interaction with dopamine D2 receptor enhances expression of transient receptor potential channel 1 at the cell surface.

Receptor signaling is mediated by direct protein interaction with various types of cytoskeletal, adapter, effector, and additional receptor molecules. In brain tissue and in cultured neurons, activation of dopamine D2 receptors (D2Rs) has been found to impact cellular calcium signaling. Using a yeast two-hybrid approach, we have uncovered a direct physical interaction between the D2R and the transient receptor potential channel (TRPC) subtypes 1, 4 and 5.

Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex.

Spatial working memory (WM; i.e., "scratchpad" memory) is constantly updated to guide behavior based on representational knowledge of spatial position.

Internalization of D2 dopamine receptors is clathrin-dependent and select to dendro-axonic appositions in primate prefrontal cortex.

Much of our knowledge on trafficking of neurotransmitter receptors derives from heterologous expression systems and neurons in vitro. Understanding these dynamics in vivo for dopamine receptors, and D2 receptors (D2Rs) in particular, presents a foremost challenge as their pharmacological manipulation underlies antipsychotic medications and drug abuse, which may in turn alter response to endogenous dopamine. Here we present the first ultrastructural evidence of clathrin-mediated endocytosis of D2Rs or any other neurotransmitter receptor in the primate brain.

Presynaptic D1 dopamine receptors in primate prefrontal cortex: target-specific expression in the glutamatergic synapse.

Dopaminergic modulation of glutamate neurotransmission in prefrontal cortex (PFC) microcircuits is commonly perceived as a basis for cognitive operations. Yet it appears that although the control of recurrent excitation between deep-layer prefrontal pyramids may involve presynaptic and postsynaptic D1 receptor (D1R) mechanisms, pyramid-to-interneuron communication will engage a postsynaptic D1R component. The substrate underlying such target-specific neuromodulatory patterns was investigated in the infragranular PFC with immunoelectron microscopy for D1R and parvalbumin, a marker for fast-spiking interneurons.

Microdomains for dopamine volume neurotransmission in primate prefrontal cortex.

The explicit yet enigmatic involvement of dopamine in cortical physiology is in part volumetric (beyond the synapse), as is apparently the action of neuroleptics targeting dopamine receptors. The notion that nonsynaptic neuronal membranes would translate extracellular dopamine into receptor-specific spatiotemporal downstream signaling, similar to the chemical synapse, is intriguing. Here, we report that dopamine D5 (but not D1 or D2) receptors in the perisomatic plasma membrane of prefrontal cortical neurons form discrete and exclusively extrasynaptic microdomains with inositol 1,4,5-trisphosphate-gated calcium stores of subsurface cisterns and mitochondria.