The recent identification of the mitochondrial Ca2+ uniporter gene (Mcu/Ccdc109a) has enabled us to address its role, and that of mitochondrial Ca2+ uptake, in neuronal excitotoxicity. Here we show that exogenously expressed Mcu is mitochondrially localized and increases mitochondrial Ca2+ levels following NMDA receptor activation, leading to increased mitochondrial membrane depolarization and excitotoxic cell death. Knockdown of endogenous Mcu expression reduces NMDA-induced increases in mitochondrial Ca2+, resulting in lower levels of mitochondrial depolarization and resistance to excitotoxicity. Mcu is subject to dynamic regulation as part of an activity-dependent adaptive mechanism that limits mitochondrial Ca2+ overload when cytoplasmic Ca2+ levels are high. Specifically, synaptic activity transcriptionally represses Mcu, via a mechanism involving the nuclear Ca2+ and CaM kinase-mediated induction of Npas4, resulting in the inhibition of NMDA receptor-induced mitochondrial Ca2+ uptake and preventing excitotoxic death. This establishes Mcu and the pathways regulating its expression as important determinants of excitotoxicity, which may represent therapeutic targets for excitotoxic disorders.

Factors that influence the activity of prefrontal cortex (PFC) pyramidal neurons are likely to play an important role in working memory function. One such factor may be the release of Ca2+ from intracellular stores. Here we investigate the hypothesis that metabotropic glutamate receptors (mGluRs)-mediated waves of internally released Ca2+ can regulate the intrinsic excitability and firing patterns of PFC pyramidal neurons. Synaptic or focal pharmacological activation of mGluRs triggered Ca2+ waves in the dendrites and somata of layer V medial PFC pyramidal neurons. These Ca2+ waves often evoked a transient SK-mediated hyperpolarization followed by a prolonged depolarization that respectively decreased and increased neuronal excitability. Generation of the hyperpolarization depended on whether the Ca2+ wave invaded or came near to the soma. The depolarization also depended on the extent of Ca2+ wave propagation. We tested factors that influence the propagation of Ca2+ waves into the soma. Stimulating more synapses, increasing inositol trisphosphate concentration near the soma, and priming with physiological trains of action potentials all enhanced the amplitude and likelihood of evoking somatic Ca2+ waves. These results suggest that mGluR-mediated Ca2+ waves may regulate firing patterns of PFC pyramidal neurons engaged by working memory, particularly under conditions that favor the propagation of Ca2+ waves into the soma.

Changes in the intracellular concentration of calcium ions in neurons are involved in neurite growth, development, and remodeling, regulation of neuronal excitability, increases and decreases in the strength of synaptic connections, and the activation of survival and programmed cell death pathways. An important aspect of the signals that trigger these processes is that they are frequently initiated in the form of glutamatergic neurotransmission within dendritic trees, while their completion involves specific changes in the patterns of genes expressed within neuronal nuclei. Accordingly, two prominent aims of research concerned with calcium signaling in neurons are determination of the mechanisms governing information conveyance between synapse and nucleus, and discovery of the rules dictating translation of specific patterns of inputs into appropriate and specific transcriptional responses. In this article, we present an overview of the avenues by which glutamatergic excitation of dendrites may be communicated to the neuronal nucleus and the primary calcium-dependent signaling pathways by which synaptic activity can invoke changes in neuronal gene expression programs.

Summary Persistent pain induced by noxious stimuli is characterized by the transition from normosensitivity to hypersensitivity. Underlying mechanisms are not well understood, although gene expression is considered important. Here we show that persistent nociceptive-like activity triggers calcium transients in neuronal nuclei within the superficial spinal dorsal horn, and that nuclear calcium is necessary for the development of long-term inflammatory hypersensitivity. Using a nucleus-specific calcium signal perturbation strategy in vivo complemented by gene profiling, bioinformatics and functional analyses, we discovered a pain-associated, nuclear calcium-regulated gene program in spinal excitatory neurons. This includes C1q, a novel modulator of synaptic spine morphogenesis, which we found to contribute to activity-dependent spine remodelling on spinal neurons in a manner functionally associated with inflammatory hypersensitivity. Thus, nuclear calcium integrates synapse-to-nucleus communication following noxious stimulation and controls a spinal genomic response that mediates the transition between acute and long-term nociceptive sensitization by modulating functional and structural plasticity.

Non-technical summary The hippocampus is a neural structure that is critical for some forms of memory function. It performs this function through the ability of its neurons to fire patterns of activity that encode information and the ability of the synaptic connections between neurons to strengthen or weaken. Glutamate, an important synaptic neurotransmitter, can activate different types of receptors, including metabotropic glutamate receptors (mGluRs). mGluRs have been shown to be important for learning and memory. It has also been shown that changes in mGluR type 5 might contribute to mental retardation and autism, suggesting that manipulation of mGluR5 might reduce their symptoms. In this study we examined how mGluR activation can activate neuron membrane channels (SK and TRPC) in hippocampal neurons that regulate their activity. Our findings suggest that mGluR activation of SK and TRPC channels are likely to be important for sculpting patterns of activity that encode information by the hippocampus.Abstract Group I metabotropic glutamate receptors (mGluRs) play an essential role in cognitive function. Their activation results in a wide array of cellular and molecular responses that are mediated by multiple signalling cascades. In this study, we focused on Group I mGluR activation of IP 3 R-mediated intracellular Ca 2+ waves and their role in activating Ca 2+ -dependent ion channels in CA1 pyramidal neurons. Using whole-cell patch-clamp recordings and high-speed Ca 2+ fluorescence imaging in acute hippocampal brain slices, we show that synaptic and pharmacological stimulation of mGluRs triggers intracellular Ca 2+ waves and a biphasic electrical response composed of a transient Ca 2+ -dependent SK channel-mediated hyperpolarization and a TRPC-mediated sustained depolarization. The generation and magnitude of the SK channel-mediated hyperpolarization depended solely on the rise in intracellular Ca 2+ concentration ([Ca 2+ ] i ), whereas the TRPC channel-mediated depolarization required both a small rise in [Ca 2+ ] i and mGluR activation. Furthermore, the TRPC-mediated current was suppressed by forskolin-induced rises in cAMP. We also show that SK-and TRPC-mediated currents robustly modulate pyramidal neuron excitability by decreasing and increasing their firing frequency, respectively. These findings provide additional evidence that mGluR-mediated synaptic transmission makes an important contribution to regulating the output of hippocampal neurons through intracellular Ca 2+ wave activation of SK and TRPC channels. cAMP provides an additional level of regulation by modulating TRPC-mediated sustained depolarization that we propose to be important for stabilizing periods of sustained firing.