SYSTEM XC- AS A MOLECULAR MECHANISM FOR EVOLUTIONARY NEW FORMS OF ADVANCED COGNITION.

Human cognitive abilities are deeply rooted in evolutionary building blocks that maximize computation while maintaining efficiency. These abilities are not without evolutionary signatures; conserved processes like vision have undergone continual phylogenetic adjustments to better serve ecological niches. Conversely, more sophisticated forms of cognition may have required evolutionary innovations to transform existing neuronal processing to expand computational abilities.

Specialized astrocytes mediate glutamatergic gliotransmission in the CNS.

Multimodal astrocyte-neuron communications govern brain circuitry assembly and function. For example, through rapid glutamate release, astrocytes can control excitability, plasticity and synchronous activity of synaptic networks, while also contributing to their dysregulation in neuropsychiatric conditions. For astrocytes to communicate through fast focal glutamate release, they should possess an apparatus for Ca-dependent exocytosis similar to neurons.

Circuit-specific control of the medial entorhinal inputs to the dentate gyrus by atypical presynaptic NMDARs activated by astrocytes.

Here, we investigated the properties of presynaptic -methyl-d-aspartate receptors (pre-NMDARs) at corticohippocampal excitatory connections between perforant path (PP) afferents and dentate granule cells (GCs), a circuit involved in memory encoding and centrally affected in Alzheimer's disease and temporal lobe epilepsy. These receptors were previously reported to increase PP release probability in response to gliotransmitters released from astrocytes. Their activation occurred even under conditions of elevated Mg and lack of action potential firing in the axons, although how this could be accomplished was unclear.

Studying Axon-Astrocyte Functional Interactions by 3D Two-Photon Ca Imaging: A Practical Guide to Experiments and "Big Data" Analysis.

Recent advances in fast volumetric imaging have enabled rapid generation of large amounts of multi-dimensional functional data. While many computer frameworks exist for data storage and analysis of the multi-gigabyte Ca imaging experiments in neurons, they are less useful for analyzing Ca dynamics in astrocytes, where transients do not follow a predictable spatio-temporal distribution pattern. In this manuscript, we provide a detailed protocol and commentary for recording and analyzing three-dimensional (3D) Ca transients through time in GCaMP6f-expressing astrocytes of adult brain slices in response to axonal stimulation, using our recently developed tools to perform interactive exploration, filtering, and time-correlation analysis of the transients.

Gliotransmission: Beyond Black-and-White.

Astrocytes are highly complex cells with many emerging putative roles in brain function. Of these, gliotransmission (active information transfer from glia to neurons) has probably the widest implications on our understanding of how the brain works: do astrocytes really contribute to information processing within the neural circuitry? "Positive evidence" for this stems from work of multiple laboratories reporting many examples of modulatory chemical signaling from astrocytes to neurons in the timeframe of hundreds of milliseconds to several minutes. This signaling involves, but is not limited to, Ca-dependent vesicular transmitter release, and results in a variety of regulatory effects at synapses in many circuits that are abolished by preventing Ca elevations or blocking exocytosis selectively in astrocytes.

Generation and Characterization of Anti-VGLUT Nanobodies Acting as Inhibitors of Transport.

The uptake of glutamate by synaptic vesicles is mediated by vesicular glutamate transporters (VGLUTs). The central role of these transporters in excitatory neurotransmission underpins their importance as pharmacological targets. Although several compounds inhibit VGLUTs, highly specific inhibitors were so far unavailable, thus limiting applications to in vitro experiments.

Three-dimensional Ca imaging advances understanding of astrocyte biology.

Astrocyte communication is typically studied by two-dimensional calcium ion (Ca) imaging, but this method has not yielded conclusive data on the role of astrocytes in synaptic and vascular function. We developed a three-dimensional two-photon imaging approach and studied Ca dynamics in entire astrocyte volumes, including during axon-astrocyte interactions. In both awake mice and brain slices, we found that Ca activity in an individual astrocyte is scattered throughout the cell, largely compartmented between regions, preponderantly local within regions, and heterogeneously distributed regionally and locally.

Topological Regulation of Synaptic AMPA Receptor Expression by the RNA-Binding Protein CPEB3.

Synaptic receptors gate the neuronal response to incoming signals, but they are not homogeneously distributed on dendrites. A spatially defined receptor distribution can preferentially amplify certain synaptic inputs, resize receptive fields of neurons, and optimize information processing within a neuronal circuit. Thus, a longstanding question is how the spatial organization of synaptic receptors is achieved.

What do we know about gliotransmitter release from astrocytes?

Astrocytes participate in information processing by actively modulating synaptic properties via gliotransmitter release. Various mechanisms of astrocytic release have been reported, including release from storage organelles via exocytosis and release from the cytosol via plasma membrane ion channels and pumps. It is still not fully clear which mechanisms operate under which conditions, but some of them, being Ca(2+)-regulated, may be physiologically relevant.

Astrocyte Ca²⁺ signalling: an unexpected complexity.

Astrocyte Ca(2+) signalling has been proposed to link neuronal information in different spatial-temporal dimensions to achieve a higher level of brain integration. However, some discrepancies in the results of recent studies challenge this view and highlight key insufficiencies in our current understanding. In parallel, new experimental approaches that enable the study of astrocyte physiology at higher spatial-temporal resolution in intact brain preparations are beginning to reveal an unexpected level of compartmentalization and sophistication in astrocytic Ca(2+) dynamics.

Ca(2+) permeable AMPA receptors switch allegiances: mechanisms and consequences.

The subunit composition of synaptic AMPA receptors can undergo dynamic changes during physiological functioning and under pathological conditions. This switch in AMPA receptor phenotype involves changes in the level of GluA2 subunits that are mediated via regulated AMPA receptor trafficking, modification of local protein synthesis and altered gene transcription of GluA2 subunits. Incorporation of the GluA2 subunits into an AMPA receptor alters a number of key biophysical properties, including Ca(2+) permeability and the waveform of the synaptic current.

Inhibition of Ca2+-activated large-conductance K+ channel activity alters synaptic AMPA receptor phenotype in mouse cerebellar stellate cells.

Many fast-spiking inhibitory interneurons, including cerebellar stellate cells, fire brief action potentials and express α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-type glutamate receptors (AMPAR) that are permeable to Ca(2+) and do not contain the GluR2 subunit. In a recent study, we found that increasing action potential duration promotes GluR2 gene transcription in stellate cells. We have now tested the prediction that activation of potassium channels that control the duration of action potentials can suppress the expression of GluR2-containing AMPARs at stellate cell synapses.

Remodeling of synaptic AMPA receptor subtype alters the probability and pattern of action potential firing.

Changes in the subunit composition of postsynaptic AMPA-type glutamate receptors can be induced at CNS synapses by neural activity and under certain pathological conditions. Fear-induced incorporation of GluR2-containing receptors at cerebellar synapses selectively prolongs the decay time of synaptic currents, whereas a switch from GluR2-lacking to GluR2-containing receptors induced by parallel fiber stimulation reduces the amplitude in addition to lengthening the duration of EPSCs. Although it is often assumed that these two forms of synaptic plasticity will alter action potential (AP) firing in the postsynaptic neuron, this has not been directly tested.

A single fear-inducing stimulus induces a transcription-dependent switch in synaptic AMPAR phenotype.

Changes in emotional state are known to alter neuronal excitability and can modify learning and memory formation. Such experience-dependent neuronal plasticity can be long-lasting and is thought to involve the regulation of gene transcription. We found that a single fear-inducing stimulus increased GluR2 (also known as Gria2) mRNA abundance and promoted synaptic incorporation of GluR2-containing AMPA receptors (AMPARs) in mouse cerebellar stellate cells.

Long-term synaptic plasticity in cerebellar stellate cells.

Inhibitory transmission controls the action potential firing rate and pattern of Purkinje cell activity in the cerebellum. A long-term change in inhibitory transmission is likely to have a profound effect on the activity of cerebellar neuronal circuits. However, little is known about how neuronal activity regulates synaptic transmission in GABAergic inhibitory interneurons (stellate/basket cells) in the cerebellar cortex.

Ceramide: from embryos to tumors.

Ceramides are ubiquitous lipids that have important functions integral to apoptotic signaling. Several therapeutic agents currently exist that induce ceramide-dependent apoptosis in cancerous cells, and a number of enzymes involved in ceramide metabolism are beginning to be recognized as potential targets for cancer therapy. Recent research shows that evasion of ceramide-dependent apoptosis is essential at the earliest stages of embryonic development and is an important mechanism of multidrug resistance.