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

Abstract

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. Previous work has focused on the localization of PDE4A and PDE4B in dlPFC, but PDE4D is also of great interest, as it is the predominant PDE4 isoform in primate association cortex, and PDE4D expression decreases with aging in human dlPFC. Here we used laser-capture microdissection transcriptomics and found that PDE4D message is enriched in pyramidal cells compared to GABAergic PV-interneurons in layer III of the human dlPFC. A parallel study in rhesus macaques using high-spatial resolution immunoelectron microscopy revealed the ultrastructural locations of PDE4D in primate dlPFC with clarity not possible in human post-mortem tissue. PDE4D was especially prominent in dendrites associated with microtubules, mitochondria, and likely smooth endoplasmic reticulum (SER). There was substantial postsynaptic labeling in dendritic spines, associated with the SER spine-apparatus near glutamatergic-like axospinous synapses, but sparse labeling in axon terminals. We also observed dense PDE4D labeling perisynaptically in astroglial leaflets ensheathing glutamatergic connections. These data suggest that PDE4D is strategically positioned to regulate cAMP signaling in dlPFC glutamatergic synapses and circuits, especially in postsynaptic compartments where it is localized to influence cAMP actions on intracellular trafficking, mitochondrial physiology, and internal calcium release.

Age‐related calcium dysregulation linked with tau pathology and impaired cognition in non‐human primates

“…G) Immunolabeling for PDE4D was present along the plasma membrane and within the intracellular space of astroglial processes, in glial leaflets ensheathing the axospinous glutamatergic‐like asymmetric synapses. A more detailed mapping of PDE4D localization in young monkey dlPFC can be found in Datta et al, 2020 53 . (H) In aged monkey (26 years) dlPFC LIII, PDE4D immunolabeling was virtually absent from dendritic shafts.…”

“…A more detailed mapping of PDE4D localization in young monkey dlPFC can be found in Datta et al, 2020. 53 A-B) Iontophoretic application of pharmacological agent S107 enhanced delay-related firing of dlPFC delay cell in aged monkeys performing a WM task. Mechanistically, S107 stabilizes pS2808-RyR2 with downstream effector protein calstabin2 to suppress excess calcium leak.…”

Studies of aging nonhuman primates illuminate the etiology of early‐stage Alzheimer's‐like neuropathology: An evolutionary perspective

“…Research in rhesus monkeys shows that PDE4D, PDE4A, and mGluR3 are concentrated on or near the SER where they regulate cAMP drive on calcium release (B.C. Carlyle et al, 2014 ; Datta, Enwright, et al, 2020 ; Datta, Leslie, et al, 2020 ; Jin et al, 2018 ). Importantly, the expression of these regulatory proteins is reduced in the aged PFC in both animals and humans (Carlyle et al, 2014 ; Datta, Enwright, et al, 2020 ; Datta, Leslie, et al, 2020 ; García‐Bea et al, 2016 ; Hernandez et al, 2018 ; Leslie et al, 2020 ; Lu et al, 2004 ), rendering the association cortices vulnerable to dysregulated cAMP‐calcium signaling.…”

Models for Evaluation of Biological Age Based on Multi-omics

“…As the dlPFC ages, the expression of PDE4D will decrease. Age-related loss of PDE4D may thus contribute to the specific vulnerability of the frontal cortex to degeneration in Alzheimer's disease and may play a critical role in normal cAMP regulation (Datta et al 2020;Leslie et al 2020) (Figure 1D).…”