The role of nuclear Ca2+ in maintaining neuronal homeostasis and brain health

Abstract

Nuclear Ca2+ has emerged as one of the most potent mediators of the dialogue between neuronal synapses and the nucleus that regulates heterochromatin states, transcription factor activity, nuclear morphology and neuronal gene expression induced by synaptic activity. Recent studies underline the importance of nuclear Ca2+ signaling in long-lasting, activity-induced adaptation and maintenance of proper brain function. Diverse forms of neuroadaptation require transient nuclear Ca2+ signaling and cyclic AMP-responsive element-binding protein (CREB1, referred to here as CREB) as its prime target, which works as a tunable switch to drive and modulate specific gene expression profiles associated with memory, pain, addiction and neuroprotection. Furthermore, a reduction of nuclear Ca2+ levels has been shown to be neurotoxic and a causal factor driving the progression of neurodegenerative disorders, as well as affecting neuronal autophagy. Because of its central role in the brain, deficits in nuclear Ca2+ signaling may underlie a continuous loss of neuroprotection in the aging brain, contributing to the pathophysiology of Alzheimer's disease. In this Review, we discuss the principles of the ‘nuclear calcium hypothesis’ in the context of human brain function and its role in controlling diverse forms of neuroadaptation and neuroprotection. Furthermore, we present the most relevant and promising perspectives for future studies.

Brief and diverse excitotoxic insults cause an increase in neuronal nuclear membrane permeability in the neonatal brain

“…Interestingly, nuclear circularity was reduced with NMDA ( Fig. 5G-H ), possibly due to an increase in activity-dependent ER invaginations into the nuclear membrane (Mozolewski et al, 2021; Oliveira et al, 2014). Therefore, these data suggest that excitotoxicity-induced increase in nuclear pore size and the resulting increase in the nuclear envelope permeability allows the translocation of a large cytoplasmatic protein, in this case, GCaMP6s, into the neuronal nucleus.…”

Epigenetic repression of cFos supports sequential formation of distinct spatial memories

“…Calcium release from the endoplasmic reticulum produces even larger [Ca 2+ ] i transients (Holbro, Grunditz, and Oertner 2009; Mellentin, Jahnsen, and Abraham 2007). Notably, nuclear [Ca 2+ ] i is a potent trigger for epigenetic modifications (Bading 2013; Mozolewski et al 2021), making it a compelling parameter to study in the context of immediate early genes (Bengtson et al 2010).…”

Potential roles of the endoplasmic reticulum stress pathway in amyotrophic lateral sclerosis

“…Ca 2+ is responsible for the transmission of neuronal depolarization and synaptic activity, and Ca 2+ homeostasis and signaling are responsible for proper synaptic plasticity and survival. Thus, disruption of Ca 2+ homeostasis affects neurotoxicity and neuronal autophagy and eventually leads to the progression of neurodegenerative disorders ( Tong et al, 2018 ; Mozolewski et al, 2021 ). The accumulation of unfolded/misfolded proteins within the ER results in stress, which is mitigated by a conserved signaling mechanism known as the highly unfolded protein response (UPR; Moon et al, 2018 ; Kadowaki and Nishitoh, 2019 ).…”