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The stressed synapse: the impact of stress

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"...it has been suggested that a large portion of the amino acid neurotransmitters sampled by microdialysis is of non-neuronal origin; that is, they may result from reverse transporter activity and/or are derived from glial cells. Nevertheless, recent evidence from rapid microelectrode measurements suggests that tail-pinch-stress-induced glutamate release is largely of neuronal origin.

In different studies using patch-clamp recordings, application of 100 nM corticosterone (which is the major glucocorticoid in rodents) to hippocampal slices rapidly enhanced the frequency of miniature excitatory postsynaptic potentials in CA1 pyramidal neurons and

reduced paired-pulse facilitation (PPF; a form of syn- aptic facilitation that reflects presynaptic release), sug- gesting that corticosterone increases glutamate release probability in this area. This rapid action of corticos- terone was found to be non-genomic and mediated by a mineralocorticoid receptor located in or near the plasma membrane (BOX 1).

Stress also has an effect on depolarization-evoked release of glutamate in the PFC and frontal cortex, as shown in studies using isolated synaptic terminals (synaptosomes) in superfusion. This method allows precise and selective measurement of endogenous or labelled neurotransmitter release (BOX 2). Rats subjected to acute footshock stress in a paradigm that induces learned helplessness*** showed a marked, rapid change in the depolarization-evoked release of glutamate. The increased release of glutamate in PFC and frontal cor- tex was dependent on glucocorticoid receptor activa- tion. The short latency of the effect suggested that the receptor acted non-genomically, although the results of patch-clamp recordings (see below) are also compatible with the timing of genomic actions. Thus, both genomic and non-genomic pathways may be involved in the effect of stress on glutamate release. A similar rapid effect of corticosterone, mediated by glucocorticoid receptors, has been shown in synaptosomes isolated from rat hippocampus. As shown by recent findings, recruit- ment of endocannabinoid signalling could be involved in the enhancement of glutamate release induced by corticosterone.

The method of synaptosomes in superfusion involves using synaptic terminals detached from whole tissue. Measuring release of endogenous glutamate can also be performed in slices of whole PFC tissue, in which the neural circuitry is preserved. Patch-clamp recordings from PFC slices from rats subjected to footshock stress showed that exposure to stress increased the amplitude of spontaneous excitatory postsynaptic potentials in pyram- idal neurons, an effect that was abolished by pretreating the rats with the antidepressant desipramine. Moreover, PPF and its calcium-dependence were decreased in PFC slices from stressed rats. Combined, these results are con- sistent with increased glutamate release, as well as with increased activation of postsynaptic ionotropic glutamate receptors, in the PFC of stressed rats.

In principle, the acute-stress-induced enhance- ment of stimulus-evoked release of glutamate may be achieved by increasing the number of synaptic vesicles that are already docked to the membrane and ready for release — the readily releasable pool (RRP) of vesicles — or by increasing the probability of release of syn- aptic vesicles, or both. At the level of presynaptic machinery, footshock stress induced an increase in the number of SNARE complexes bound to the presynaptic membrane from PFC neurons (FIG. 2), suggesting that at least the first mechanism is involved. Indeed, induc- ing glutamate release with hyperosmotic sucrose from synaptosomes in superfusion from the PFC and fron- tal cortex of rats exposed to footshock stress revealed that the RRP was about twofold that of control rats. Preliminary data obtained using total internal reflection fluorescence microscopy to measure the recruitment to the membrane of synaptic vesicles labelled with the styryl dye FM1-43 also suggest a greater RRP after in vitro application of corticosterone to PFC and frontal cortex synaptosomes59.

Interestingly, the effect of acute stress on depolar- ization-evoked glutamate release in the PFC could be prevented by treating the rats with various classes of antidepressant drugs, each with different primary mechanisms of action, for 2 weeks before the stress exposure. The mechanism whereby antidepressant drugs block the presynaptic effect of stress on depolari- zation-evoked glutamate release is unknown at present. Stress-induced serum corticosterone levels were similar in antidepressant-treated and untreated rats, suggest- ing that the drugs do not alter corticosterone release.

(Learned helplessness:

Reduced attempts to avoid aversive stimuli in response to prior exposure to unavoidable stressors. Learned helplessness decreases after antidepressant administration.) .....antidepressant drugs reduce the release of glutamate in the hippocampus (in rats kept under basal conditions) and prevent the increase induced by acute stress in prefrontal and frontal cortex.....

....Glutamate can be synthesized de novo from glucose in astrocytes via the Krebs cycle, followed by transami- nation or reductive amination of a-oxoglutarate, and it can be recycled through the glutamate–glutamine cycle. Exocytotic vesicular release of glutamate, which underlies the vast majority of excitatory neurotransmission in the brain, is a strictly regulated process in which the synaptic vesicles that store glutamate merge and then fuse with the presynaptic membrane in response to stimulation."

[This is all from the article above].

***This goes along with the strained cow-calf relations, nurture-based physiologic changes, abandonment, and childhood trauma -lines of thought (..and how there may be no physiological difference between these things and anxiety/panic disorders).

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