Abstract
Neurons in the association cortices are particularly vulnerable in cognitive disorders such as schizophrenia and Alzheimer’s disease, while those in primary visual cortex remain relatively resilient. This review proposes that the special molecular mechanisms needed for higher cognitive operations confer vulnerability to dysfunction, atrophy, and neurodegeneration when regulation is lost due to genetic and/or environmental insults. Accumulating data suggest that higher cortical circuits rely on magnified levels of calcium (from NMDAR, calcium channels, and/or internal release from the smooth endoplasmic reticulum) near the postsynaptic density to promote the persistent firing needed to maintain, manipulate, and store information without “bottom-up” sensory stimulation. For example, dendritic spines in the primate dorsolateral prefrontal cortex (dlPFC) express the molecular machinery for feedforward, cAMP–PKA–calcium signaling. PKA can drive internal calcium release and promote calcium flow through NMDAR and calcium channels, while in turn, calcium activates adenylyl cyclases to produce more cAMP–PKA signaling. Excessive levels of cAMP–calcium signaling can have a number of detrimental effects: for example, opening nearby K+ channels to weaken synaptic efficacy and reduce neuronal firing, and over a longer timeframe, driving calcium overload of mitochondria to induce inflammation and dendritic atrophy. Thus, calcium–cAMP signaling must be tightly regulated, e.g., by agents that catabolize cAMP or inhibit its production (PDE4, mGluR3), and by proteins that bind calcium in the cytosol (calbindin). Many genetic or inflammatory insults early in life weaken the regulation of calcium–cAMP signaling and are associated with increased risk of schizophrenia (e.g., GRM3). Age-related loss of regulatory proteins which result in elevated calcium–cAMP signaling over a long lifespan can additionally drive tau phosphorylation, amyloid pathology, and neurodegeneration, especially when protective calcium binding proteins are lost from the cytosol. Thus, the “genie” we need for our remarkable cognitive abilities may make us vulnerable to cognitive disorders when we lose essential regulation.
Highlights
The primate cortex performs an extraordinary number and range of operations decoding sensory events, integrating sensory inputs with previous experience, and representing information in higher networks independent of sensory stimulation to create our “mental sketch pad” and generate goals for action
Emerging data suggest that the molecular mechanisms needed to sustain persistent firing in dorsolateral prefrontal cortex (dlPFC) are very different from those required to accurately decode a sensory stimulus in primary visual cortex (V1)
The current review describes the differences in neurotransmission and neuromodulation between newly evolved vs. primary sensory cortices, and speculates on how these disparities may underlie the susceptibility of dlPFC circuits in mental disorders
Summary
The primate cortex performs an extraordinary number and range of operations decoding sensory events, integrating sensory inputs with previous experience, and representing information in higher networks independent of sensory stimulation to create our “mental sketch pad” and generate goals for action. We hypothesize that modest levels of cAMP drive on calcium release near the synapse helps to maintain depolarization of the PSD, but that higher levels open sufficient K+ channels to weaken connectivity and reduce firing, producing a narrow inverted-U dose–response Both NE α1-AR and DA D1R have an inverted-U dose/ response on dlPFC persistent firing and working memory function through activation of calcium–cAMP signaling in spines (Fig. 4): moderate levels are essential, but excessive levels reduce firing and cognition through opening of nearby K+ channels [53, 72, 74, 75]. This hypothesis is supported by physiological data from monkeys, where local inhibition of GCPII enhances delay cell firing [73] (Fig. 6d). These data suggest that neurons that require high levels of internal calcium signaling for their normative functioning must express correspondingly high levels of calbindin in their cytosol for adequate protection, and that loss of calbindin with stress and/or age confers tremendous vulnerability to amyloid and tau pathology, atrophy, and/or neurodegeneration depending on the subcellular location(s) of the calcium dysregulation, and the time course of the dysregulating events [179]
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