Extracellular glutamate of glial origin modulates glial and neuronal glutamate release and synaptic plasticity. Estimates of the tonic basal concentration of extracellular glutamate range over three orders of magnitude (0.02–20 μM) depending on the technology employed to make the measurement. Based upon binding constants for glutamate receptors and transporters, this range of concentrations translates into distinct physiological and pathophysiological roles for extracellular glutamate. Here we speculate that the difference in glutamate measurements can be explained if there is patterned membrane surface expression of glutamate release and transporter sites creating extracellular subcompartments that vary in glutamate concentration and are preferentially sampled by different technologies.

The basolateral amygdala plays an important role in the acquisition and expression of both fear conditioning and fear extinction. To understand how a single structure could encode these "opposite" memories, we developed a biophysical network model of the lateral amygdala (LA) neurons during auditory fear conditioning and extinction. Membrane channel properties were selected to match waveforms and firing properties of pyramidal cells and interneurons in LA, from published in vitro studies. Hebbian plasticity was implemented in excitatory AMPA and inhibitory GABA(A) receptor-mediated synapses to model learning. The occurrence of synaptic potentiation versus depression was determined by intracellular calcium levels, according to the calcium control hypothesis. The model was able to replicate conditioning- and extinction-induced changes in tone responses of LA neurons in behaving rats. Our main finding is that LA activity during both acquisition and extinction can be controlled by a balance between pyramidal cell and interneuron activations. Extinction training depressed conditioned synapses and also potentiated local interneurons, thereby inhibiting the responses of pyramidal cells to auditory input. Both long-term depression and potentiation of inhibition were required to initiate and maintain extinction. The model provides insights into the sites of plasticity in conditioning and extinction, the mechanism of spontaneous recovery, and the role of amygdala NMDA receptors in extinction learning.

Dysfunctions in brain cholesterol homeostasis have been extensively related to brain disorders. The main pathway for brain cholesterol elimination is its hydroxylation into 24S-hydroxycholesterol by the cholesterol 24-hydrolase, CYP46A1. Increasing evidence suggests that CYP46A1 has a role in the pathogenesis and progression of neurodegenerative disorders, and that increasing its levels in the brain is neuroprotective. However, the mechanisms underlying this neuroprotection remain to be fully understood. Huntington’s disease is a fatal autosomal dominant neurodegenerative disease caused by an abnormal CAG expansion in huntingtin’s gene. Among the multiple cellular and molecular dysfunctions caused by this mutation, altered brain cholesterol homeostasis has been described in patients and animal models as a critical event in Huntington’s disease. Here, we demonstrate that a gene therapy approach based on the delivery of CYP46A1, the rate-limiting enzyme for cholesterol degradation in the brain, has a long-lasting neuroprotective effect in Huntington’s disease and counteracts multiple detrimental effects of the mutated huntingtin. In zQ175 Huntington’s disease knock-in mice, CYP46A1 prevented neuronal dysfunctions and restored cholesterol homeostasis. These events were associated to a specific striatal transcriptomic signature that compensates for multiple mHTT-induced dysfunctions. We thus explored the mechanisms for these compensations and showed an improvement of synaptic activity and connectivity along with the stimulation of the proteasome and autophagy machineries, which participate to the clearance of mutant huntingtin (mHTT) aggregates. Furthermore, BDNF vesicle axonal transport and TrkB endosome trafficking were restored in a cellular model of Huntington’s disease. These results highlight the large-scale beneficial effect of restoring cholesterol homeostasis in neurodegenerative diseases and give new opportunities for developing innovative disease-modifying strategies in Huntington’s disease.

Neurons and networks undergo a process of homeostatic plasticity that stabilizes output by integrating activity levels with network and cellular properties to counter longer-term perturbations. Here we describe a rapid compensatory interaction among a pair of potassium currents, I A and I KCa , that stabilizes both intrinsic excitability and network function in the cardiac ganglion of the crab, Cancer borealis. We determined that mRNA levels in single identified neurons for the channels which encode I A and I KCa are positively correlated, yet the ionic currents themselves are negatively correlated, across a population of motor neurons. We then determined that these currents are functionally coupled; decreasing levels of either current within a neuron causes a rapid increase in the other. This functional interdependence results in homeostatic stabilization of both the individual neuronal and the network output. Furthermore, these compensatory increases are mechanistically independent, suggesting robustness in the maintenance of neural network output that is critical for survival. Together, we generate a complete model for homeostatic plasticity from mRNA to network output where rapid posttranslational compensatory mechanisms acting on a reservoir of channels proteins regulated at the level of gene expression provide homeostatic stabilization of both cellular and network activity.

Motor neurons of the crustacean cardiac ganglion generate virtually identical, synchronized output despite the fact that each neuron uses distinct conductance magnitudes. As a result of this variability, manipulations that target ionic conductances have distinct effects on neurons within the same ganglion, disrupting synchronized motor neuron output that is necessary for proper cardiac function. We hypothesized that robustness in network output is accomplished via plasticity that counters such destabilizing influences. By blocking high-threshold K+ conductances in motor neurons within the ongoing cardiac network, we discovered that compensation both resynchronized the network and helped restore excitability. Using model findings to guide experimentation, we determined that compensatory increases of both GA and electrical coupling restored function in the network. This is one of the first direct demonstrations of the physiological regulation of coupling conductance in a compensatory context, and of synergistic plasticity across cell- and network-level mechanisms in the restoration of output.DOI: http://dx.doi.org/10.7554/eLife.16879.001