The genie in the bottle-magnified calcium signaling in dorsolateral prefrontal cortex

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.

NMDAR Neurotransmission Needed for Persistent Neuronal Firing: Potential Roles in Mental Disorders

“…In contrast to the dlPFC, high levels of catecholamines and glucocorticoids enhance the affective functioning of the amygdala (81)(82)(83), thus flipping the brain from a reflective to reflexive state. The rapid loss of dlPFC executive and working memory functions from a hypercatecholaminergic state has now been documented in humans (84)(85)(86) in addition to the original studies in rodents and monkeys (9,77,78). Thus, BA25 and amygdala can rapidly remove their regulation from higher order PFC circuits through activation of excessive catecholamine release in these higher PFC regions (Figure 4B).…”

“…(B) The increasing timescales across the primate cortical hierarchy, and their relationship to GRIN2B expression. Based on (11) and (9). LIP, lateral intraparietal cortex; MT, middle temporal visual cortex.…”

“…The PFC and cingulate cortices receive catecholamine innervation (68) and can also regulate the activity of the monoamine nuclei in the brainstem (18, 63,69). The dlPFC requires moderate levels of catecholamines to function, but high levels of catecholamines released during even mild uncontrollable stress rapidly take the dlPFC "offline" [reviewed in (9,70)]. Studies in rodents have shown that psychological stressors or threatening stimuli activate projections from the amygdala, e.g., to the locus coeruleus, increasing catecholamine release in the medial PFC (71)(72)(73)(74)(75)(76).…”

“…Although previous research in rodent classic circuits had found that NMDA-GluN2B were mostly at extra-synaptic locations (5), or played a role only in immature neurons (6), more recent research has shown that GluN2B play a critical, synaptic role in the primate cortical circuits mediating higher cognition, providing the synaptic events that generate sustained representations of visual space in working memory in the dlPFC (7,8). The high levels of calcium influx into spines may be especially important for maintaining a depolarized post-synaptic membrane, permitting continued neural firing needed to sustain representations over long time periods (9). Recent research has also shown that expression of NMDAR with GluN2B subunits encoded by the GRIN2B gene expands across primate cortical evolution (10), and across the cortical hierarchy in humans, with especially high levels in association and limbic cortices such as the anterior cingulate cortex (11).…”

Frontal lobe fALFF measured from resting-state fMRI at baseline predicts acute treatment response in first episode psychosis

“…Several task-based fMRI studies have suggested that normalization of hypoactivity in the dorsal prefrontal cortex may be a marker of antipsychotic efficacy 69 , consistent with results of cross-sectional studies comparing treatment-resistant to treatment-responsive patients with schizophrenia 70 . A mechanistic understanding of dorsal prefrontal cortex suggests that tight regulation of calcium-cAMP signaling is required for optimal function, and that several pharmacologic approaches may be tested that can ameliorate calcium dysregulation 71 . Intriguingly, emerging evidence suggests that non-pharmacologic approaches to schizophrenia treatment such as repetitive transcranial magnetic stimulation (rTMS) and cognitive remediation therapy may also effectively modulate activity and connectivity in the dorsal prefrontal cortex 72 .…”