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Craig E Jahr

Publications and source records attributed to Craig E Jahr.

12 recordsLinked to original sources
PubMed2006

Exocytosis unbound.

The accepted theory of vesicular release of neurotransmitter posits that only a single vesicle per synapse can fuse with the membrane following action potential invasion, and this exocytotic event is limited to the ultrastructurally defined presynaptic active zone. Neither of these dictums is universally true. At certain synapses, more than a single vesicle can be released per action potential, and there is growing evidence that neuronal exocytosis can occur from sites that are unremarkable in electron micrographs. The first discrepancy extends the dynamic range of synapses, whereas the second enables faster and more robust chemical transmission at sites distant from morphologically defined synapses. Taken together, these attributes expand the capabilities of cellular communication in the nervous system.

Action Potentials↗
PubMed2006

Intrinsic kinetics determine the time course of neuronal synaptic transporter currents.

Efficient clearance of synaptically released glutamate from the extracellular space is an absolute requirement for maintaining information processing in the central nervous system. In the cerebellum, clearance of glutamate relies on uptake by Bergmann glial cells and Purkinje cells (PCs). Uptake by PCs can be monitored by recording the synaptic transport current (STC) mediated by the PC-specific transporter excitatory amino acid transporter 4 (EAAT4). The slow time course of the PC STC has been used to argue that glutamate clearance is protracted. We find, however, that the time course of the STC is not affected by altering the amount of glutamate released at individual synapses or by partial transporter blockade, manipulations that would be expected to change the duration of the extracellular glutamate transient. Ion substitution experiments and kinetic modeling of the PC transporter current suggest that physiological levels of intracellular Na(+) and glutamate slow the cycling rate of transporters and thereby lengthen the time course of STCs. The model predicts that PC transporters bind glutamate quickly but that the actual cycling rate of EAAT4 in physiological conditions is slow; therefore, the STC reflects the intrinsic kinetics of the glutamate transporter, not the rate of glutamate clearance.

Animals↗
PubMed2006

Multivesicular release at Schaffer collateral-CA1 hippocampal synapses.

Whether an individual synapse releases single or multiple vesicles of transmitter per action potential is contentious and probably depends on the type of synapse. One possibility is that multivesicular release (MVR) is determined by the instantaneous release probability (Pr) and therefore can be controlled by activity-dependent changes in Pr. We investigated transmitter release across a range of Pr at synapses between Schaffer collaterals (SCs) and CA1 pyramidal cells in acute hippocampal slices using patch-clamp recordings. The size of the synaptic glutamate transient was estimated by the degree of inhibition of AMPA receptor EPSCs with the rapidly equilibrating antagonist gamma-D-glutamylglycine. The glutamate transient sensed by AMPA receptors depended on Pr but not spillover, indicating that multiple vesicles are essentially simultaneously released from the same presynaptic active zone. Consistent with an enhanced glutamate transient, increasing Pr prolonged NMDA receptor EPSCs when glutamate transporters were inhibited. We suggest that MVR occurs at SC-CA1 synapses when Pr is elevated by facilitation and that MVR may be a phenomenon common to many synapses throughout the CNS.

Action Potentials↗
PubMed2005

Patterned expression of Purkinje cell glutamate transporters controls synaptic plasticity.

Glutamate transporters are responsible for clearing synaptically released glutamate from the extracellular space. If expressed at high enough densities, transporters can prevent activation of extrasynaptic receptors by rapidly lowering glutamate concentrations to insignificant levels. We find that synaptic activation of metabotropic glutamate receptors expressed by Purkinje cells is prevented in regions of rat cerebellum where the density of the glutamate transporter EAAT4 is high. The consequences of metabotropic receptor stimulation, including activation of a depolarizing conductance, cannabinoid-mediated presynaptic inhibition and long-term depression, are also limited in Purkinje cells expressing high levels of EAAT4. We conclude that neuronal uptake sites must be overwhelmed by glutamate to activate perisynaptic metabotropic glutamate receptors. Regional differences in glutamate transporter expression affect the degree of metabotropic glutamate receptor activation and therefore regulate synaptic plasticity.

Analysis of Variance↗
PubMed2005

High-concentration rapid transients of glutamate mediate neural-glial communication via ectopic release.

Until recently, communication from neurons to astrocytes was thought to be mediated by low-concentration transients of glutamate caused by spillover from the synaptic cleft. However, quantal events recorded in rat cerebellar Bergmann glial cells (BGs) have fast kinetics, comparable with those recorded in neurons. By combining outside-out patch recordings of BG AMPA receptors and quantitative electron microscopic analysis of glutamate receptor subunit 1 (GluR1) and GluR4 immunogold labeling measurements, at both the soma and membranes surrounding synapses, we estimate the absolute density of functional AMPA receptors. Using a kinetic model of BG AMPA receptors, we find that quantal events recorded in BGs are produced by high-concentration (approximately 1-1.5 mM), fast transients (approximately 0.5 ms decay) of glutamate, similar to transients within the synaptic cleft. Our results indicate that neural signaling to BGs is mediated by ectopic release of transmitter from presynaptic elements directly facing the BG membrane.

Animals↗
PubMed2004

Differential control of synaptic and ectopic vesicular release of glutamate.

Exocytosis of synaptic vesicles occurs not only at synaptic active zones but also at ectopic sites. Ectopic exocytosis provides a direct and rapid mechanism for neurons to communicate with glia that does not rely on transmitter spillover from the synaptic cleft. In the cerebellar cortex the processes of Bergmann glia cells encase synapses between presynaptic climbing fiber varicosities and postsynaptic Purkinje cell spines and express both AMPA receptors and electrogenic glutamate transporters. AMPA receptors expressed by Purkinje cells and Bergmann glia cells are activated predominantly by synaptic and ectopic release, respectively, and therefore can be used to compare the properties of the two release mechanisms. We report that vesicular release differs at synaptic and ectopic sites in the magnitude of short-term plasticity and the proportions of Ca2+ channel subtypes that trigger glutamate release. High-affinity glutamate transporter-mediated currents in Bergmann glia cells follow the rules of synaptic release more closely than the rules of ectopic release, indicating that the majority of glutamate is released from conventional synapses. On the other hand, ectopic release produces high-concentration glutamate transients at Bergmann glia cell membranes that are necessary to activate low-affinity AMPA receptors rapidly. Ectopic release may provide a geographical cue to guide Bergmann glia cell membranes to surround active synapses and ensure efficient uptake of glutamate that diffuses out of the synaptic cleft.

Amino Acid Transport System X-AG↗
PubMed2003

Ectopic release of synaptic vesicles.

Exocytosis of synaptic vesicles is generally assumed to occur only at ultrastructurally defined presynaptic active zones. If release is restricted to these sites, receptors not located within the synaptic cleft must be activated by transmitter that diffuses out of the cleft or not be activated at all. Here we report that AMPA receptor-mediated quantal events resulting from climbing fiber release are observed in Bergmann glial cells in the cerebellar cortex. These quantal events are not coincident with quanta recorded in neighboring Purkinje cells which receive input from the same climbing fiber. As Bergmann glial membranes are excluded from the synaptic cleft, we propose that exocytosis can occur from climbing fiber release sites located directly across from Bergmann glial membranes. Such ectopic release may account for the majority of the Bergmann glial AMPA response evoked by climbing fiber stimulation.

Animals↗
PubMed2003

Receptor occupancy limits synaptic depression at climbing fiber synapses.

Postsynaptic responses to presynaptic stimulation are used regularly to assess the amount of transmitter released from presynaptic release zones. At climbing fiber-to-Purkinje cell synapses, the number of vesicles released per active zone follows changes in release probability such that, normally, more than one vesicle is released per presynaptic action potential. This leads to high occupation of postsynaptic AMPA receptors by glutamate and thus may render the postsynaptic response relatively insensitive to changes in release. We find that paired-pulse depression of presynaptic release is not accurately represented by postsynaptic responses because of receptor saturation. By lowering vesicular glutamate concentrations or by using nonsaturated Bergmann glial AMPA receptors to monitor presynaptic release, we find that presynaptic depression of release is much greater than suggested previously. In addition, densely expressed glutamate transporters can shield Bergmann glial AMPA receptors and presynaptic metabotropic glutamate receptors from activation.

Animals↗
PubMed2002

Comparison of coupled and uncoupled currents during glutamate uptake by GLT-1 transporters.

The transport of glutamate across the plasma membrane is coupled to the movement of cations (Na+, K+, and H+) that are necessary for glutamate uptake and transporter cycling as well as anions that are uncoupled from the flux of glutamate. Although the relationship between these coupled (stoichiometric) and uncoupled (anion) transporter currents is poorly understood, transporter-associated anion currents often are used to monitor transporter activity. To define the kinetic relationship between these two components, we have recorded transporter currents associated with stoichiometric and anion charge movements occurring in response to the rapid application of l-glutamate to outside-out patches from human embryonic kidney cells expressing GLT-1 transporters. Transporter-associated anion currents were approximately twice as slow to rise and decay as stoichiometric transport currents, but the presence of permeant anions did not slow transporter cycling. A kinetic model for GLT-1 was developed to simulate the behavior of both components of the transporter current and to estimate the capture efficiency of GLT-1. In this model the K+ counter-transport step was defined as rate-limiting, consistent with the slowing of transporter cycling after the substitution of internal K+ with Cs+ or Na+. The model predicts that in physiological conditions approximately 35% of GLT-1 transporters function as buffers, releasing glutamate back into the extracellular space after binding.

Biological Transport↗
PubMed2002

Kainate receptors differentially regulate release at two parallel fiber synapses.

Presynaptic kainate receptors (KARs) facilitate or depress transmitter release at several synapses in the CNS. Here, we report that synaptically activated KARs presynaptically facilitate and depress transmission at parallel fiber synapses in the cerebellar cortex. Low-frequency stimulation of parallel fibers facilitates synapses onto both stellate cells and Purkinje cells, whereas high-frequency stimulation depresses stellate cell synapses but continues to facilitate Purkinje cell synapses. These effects are mimicked by exogenous KAR agonists and eliminated by blocking KARs. This differential frequency-dependent sensitivity of these two synapses regulates the balance of excitatory and inhibitory input to Purkinje cells and therefore their excitability.

Amino Acid Transport System X-AG↗
PubMed2002

Self-inhibition of olfactory bulb neurons.

The GABA (gamma-aminobutyric-acid)-containing periglomerular (PG) cells provide the first level of inhibition to mitral and tufted (M/T) cells, the output neurons of the olfactory bulb. We find that stimulation of PG cells of the rat olfactory bulb results in self-inhibition: release of GABA from an individual PG cell activates GABA(A) receptors on the same neuron. PG cells normally contain high concentrations of intracellular chloride and consequently are depolarized by GABA. Despite this, GABA inhibits PG cell firing by shunting excitatory signals. Finally, GABA released during self-inhibition may spill over to neighboring PG cells, resulting in a lateral spread of inhibition. Given the gatekeeping role of PG cells in the olfactory network, GABA-mediated self-inhibition will favor M/T cell excitation during intense sensory stimulation.

Animals↗