Glutamate uptake is transiently compromised in the perilesional cortex following controlled cortical impact.

Glutamate, the primary excitatory neurotransmitter in the CNS, is regulated by the excitatory amino acid transporters (EAATs) GLT-1 and GLAST. Following traumatic brain injury (TBI), extracellular glutamate levels increase, contributing to excitotoxicity, circuit dysfunction, and morbidity. Increased neuronal glutamate release and compromised astrocyte-mediated uptake contribute to elevated glutamate, but the mechanistic and spatiotemporal underpinnings of these changes are not well established.

Kir4.1 channels contribute to astrocyte CO/H-sensitivity and the drive to breathe.

Astrocytes in the retrotrapezoid nucleus (RTN) stimulate breathing in response to CO/H, however, it is not clear how these cells detect changes in CO/H. Considering Kir4.1/5.

Traumatic brain injury disrupts state-dependent functional cortical connectivity in a mouse model.

Traumatic brain injury (TBI) is the leading cause of death in young people and can cause cognitive and motor dysfunction and disruptions in functional connectivity between brain regions. In human TBI patients and rodent models of TBI, functional connectivity is decreased after injury. Recovery of connectivity after TBI is associated with improved cognition and memory, suggesting an important link between connectivity and functional outcome.

Cortical Parvalbumin-Positive Interneuron Development and Function Are Altered in the APC Conditional Knockout Mouse Model of Infantile and Epileptic Spasms Syndrome.

Infantile and epileptic spasms syndrome (IESS) is a childhood epilepsy syndrome characterized by infantile or late-onset spasms, abnormal neonatal EEG, and epilepsy. Few treatments exist for IESS, clinical outcomes are poor, and the molecular and circuit-level etiologies of IESS are not well understood. Multiple human IESS risk genes are linked to Wnt/β-catenin signaling, a pathway that controls developmental transcriptional programs and promotes glutamatergic excitation via β-catenin's role as a synaptic scaffold.

Neuronal activity drives pathway-specific depolarization of peripheral astrocyte processes.

Astrocytes are glial cells that interact with neuronal synapses via their distal processes, where they remove glutamate and potassium (K) from the extracellular space following neuronal activity. Astrocyte clearance of both glutamate and K is voltage dependent, but astrocyte membrane potential (V) is thought to be largely invariant. As a result, these voltage dependencies have not been considered relevant to astrocyte function.

Effects of fluorescent glutamate indicators on neurotransmitter diffusion and uptake.

Genetically encoded fluorescent glutamate indicators (iGluSnFRs) enable neurotransmitter release and diffusion to be visualized in intact tissue. Synaptic iGluSnFR signal time courses vary widely depending on experimental conditions, often lasting 10-100 times longer than the extracellular lifetime of synaptically released glutamate estimated with uptake measurements. iGluSnFR signals typically also decay much more slowly than the unbinding kinetics of the indicator.

Tonic Activation of GluN2C/GluN2D-Containing NMDA Receptors by Ambient Glutamate Facilitates Cortical Interneuron Maturation.

Developing cortical GABAergic interneurons rely on genetic programs, neuronal activity, and environmental cues to construct inhibitory circuits during early postnatal development. Disruption of these events can cause long-term changes in cortical inhibition and may be involved in neurological disorders associated with inhibitory circuit dysfunction. We hypothesized that tonic glutamate signaling in the neonatal cortex contributes to, and is necessary for, the maturation of cortical interneurons.

Glutamate Clearance Is Locally Modulated by Presynaptic Neuronal Activity in the Cerebral Cortex.

Unlabelled: Excitatory amino acid transporters (EAATs) are abundantly expressed by astrocytes, rapidly remove glutamate from the extracellular environment, and restrict the temporal and spatial extent of glutamate signaling. Studies probing EAAT function suggest that their capacity to remove glutamate is large and does not saturate, even with substantial glutamate challenges. In contrast, we report that neuronal activity rapidly and reversibly modulates EAAT-dependent glutamate transport.

Astrocytic glutamate uptake is slow and does not limit neuronal NMDA receptor activation in the neonatal neocortex.

Glutamate uptake by astrocytes controls the time course of glutamate in the extracellular space and affects neurotransmission, synaptogenesis, and circuit development. Astrocytic glutamate uptake has been shown to undergo post-natal maturation in the hippocampus, but has been largely unexplored in other brain regions. Notably, glutamate uptake has never been examined in the developing neocortex.

WONOEP appraisal: molecular and cellular imaging in epilepsy.

Great advancements have been made in understanding the basic mechanisms of ictogenesis using single-cell electrophysiology (e.g., patch clamp, sharp electrode), large-scale electrophysiology (e.

Control and plasticity of the presynaptic action potential waveform at small CNS nerve terminals.

The steep dependence of exocytosis on Ca(2+) entry at nerve terminals implies that voltage control of both Ca(2+) channel opening and the driving force for Ca(2+) entry are powerful levers in sculpting synaptic efficacy. Using fast, genetically encoded voltage indicators in dissociated primary neurons, we show that at small nerve terminals K(+) channels constrain the peak voltage of the presynaptic action potential (APSYN) to values much lower than those at cell somas. This key APSYN property additionally shows adaptive plasticity: manipulations that increase presynaptic Ca(2+) channel abundance and release probability result in a commensurate lowering of the APSYN peak and narrowing of the waveform, while manipulations that decrease presynaptic Ca(2+) channel abundance do the opposite.

Laser-scanning astrocyte mapping reveals increased glutamate-responsive domain size and disrupted maturation of glutamate uptake following neonatal cortical freeze-lesion.

Astrocytic uptake of glutamate shapes extracellular neurotransmitter dynamics, receptor activation, and synaptogenesis. During development, glutamate transport becomes more robust. How neonatal brain insult affects the functional maturation of glutamate transport remains unanswered.

Dynamin phosphorylation controls optimization of endocytosis for brief action potential bursts.

Modulation of synaptic vesicle retrieval is considered to be potentially important in steady-state synaptic performance. Here we show that at physiological temperature endocytosis kinetics at hippocampal and cortical nerve terminals show a bi-phasic dependence on electrical activity. Endocytosis accelerates for the first 15-25 APs during bursts of action potential firing, after which it slows with increasing burst length creating an optimum stimulus for this kinetic parameter.

Overlapping role of dynamin isoforms in synaptic vesicle endocytosis.

The existence of neuron-specific endocytic protein isoforms raises questions about their importance for specialized neuronal functions. Dynamin, a GTPase implicated in the fission reaction of endocytosis, is encoded by three genes, two of which, dynamin 1 and 3, are highly expressed in neurons. We show that dynamin 3, thought to play a predominantly postsynaptic role, has a major presynaptic function.

Synaptic vesicle retrieval time is a cell-wide rather than individual-synapse property.

Although individual nerve terminals from the same neuron often differ in neurotransmitter release characteristics, the extent to which endocytic retrieval of synaptic vesicle components differs is unknown. We used high-fidelity optical recordings to undertake a large-scale analysis of endocytosis kinetics of individual boutons in hippocampal rat neurons. Our data indicate that endocytosis kinetics do not differ substantially across boutons from the same cell but instead appear to be controlled at a cell-wide level.

Calcium control of endocytic capacity at a CNS synapse.

The ability to recycle synaptic vesicles is a crucial property of nerve terminals that allows maintenance of synaptic transmission. Using high-sensitivity optical approaches at hippocampal nerve terminals in dissociated neurons in culture, we show that modulation of endocytosis can be achieved by expansion of the endocytic capacity. Our experiments indicate that the endocytic capacity, the maximum number of synaptic vesicles that can be internalized in parallel at individual synapses, is tightly controlled by intracellular calcium levels.