Long-term Potentiation Of Transmission Research Articles

Mitragynine inhibits hippocampus neuroplasticity and its molecular mechanism

BackgroundMitragynine (MIT), the primary indole alkaloid of kratom (Mitragyna speciosa), has been associated with addictive and cognitive decline potentials. In acute studies, MIT decreases spatial memory and inhibits hippocampal synaptic transmission in long-term potentiation (LTP). This study investigated the impacts of 14-day MIT treatment on hippocampus synaptic transmission and its possible underlying mechanisms.MethodsUnder urethane anesthesia, field excitatory post-synaptic potentials (fEPSP) of the hippocampal CA1 region were recorded in the Sprague Dawley (SD) rats that received MIT (1, 5, and 10 mg/kg), morphine (MOR) 5 mg/kg, or vehicle (ip). The effects of the treatments on basal synaptic transmission, paired-pulse facilitation (PPF), and LTP were assessed in the CA1 region. Analysis of the brain's protein expression linked to neuroplasticity was then performed using a western blot.ResultsThe baseline synaptic transmission's amplitude was drastically decreased by MIT at 5 and 10 mg/kg doses, although the PPF ratio before TBS remained unchanged, the PPF ratio after TBS was significantly reduced by MIT (10 mg/kg). Strong and persistent inhibition of LTP was generated in the CA1 region by MIT (5 and 10 mg/kg) doses; this effect was not seen in MIT (1 mg/kg) treated rats. In contrast to MIT (1 mg/kg), MIT (5 and 10 mg/kg) significantly raised the extracellular glutamate levels. After exposure to MIT, GluR-1 receptor expression remained unaltered. However, NMDAε2 receptor expression was markedly downregulated. The expression of pCaMKII, pERK, pCREB, BDNF, synaptophysin, PSD-95, Delta fosB, and CDK-5 was significantly downregulated in response to MIT (5 and 10 mg/kg) exposure, while MOR (5 mg/kg) significantly raised synaptophysin and Delta fosB expression.ConclusionFindings from this work reveal that a smaller dose of MIT (1 mg/kg) poses no risk to hippocampal synaptic transmission. Alteration in neuroplasticity-associated proteins may be a molecular mechanism for MIT (5 and 10 mg/kg)-induced LTP disruption and cognitive impairments. Data from this work posit that MIT acted differently from MOR on neuroplasticity and its underlying mechanisms.Graphical abstract

AMPA Receptor Incorporation into Synapses during LTP: The Role of Lateral Movement and Exocytosis

The regulated trafficking of AMPA receptors (AMPARs) to synapses is thought to underlie the enhanced transmission in long-term potentiation (LTP), a cellular model of memory. However, there is controversy regarding the nonsynaptic site, either on the surface or intracellularly, from which AMPARs move into synapses during LTP. Using recombinant surface-fluorescent receptors in organotypic rat hippocampal slices, we show that the majority of AMPARs incorporated into synapses during LTP is from lateral diffusion of spine surface receptors containing GluR1, an AMPAR subunit. Following synaptic potentiation, AMPARs in intracellular pools containing GluR1 are driven to the surface primarily on dendrites. These exocytosed receptors likely serve to replenish the local extrasynaptic pool available for subsequent bouts of plasticity. These results clarify the role of intracellular and surface AMPARs during synaptic plasticity.

Making sense of AMPA receptor trafficking by modeling molecular mechanisms of synaptic plasticity

Synaptic plasticity involves a complex molecular machinery with various protein interactions but it is not yet clear how its components give rise to the different aspects of synaptic plasticity. Here we ask whether it is possible to mathematically model synaptic plasticity by making use of known substances only. We present a model of a multistable biochemical reaction system and use it to simulate the plasticity of synaptic transmission in long-term potentiation (LTP) or long-term depression (LTD) after repeated excitation of the synapse. According to our model, we can distinguish between two phases: first, a “viscosity” phase after the first excitation, the effects of which like the activation of NMDA receptors and CaMKII fade out in the absence of further excitations. Second, a “plasticity” phase actuated by an identical subsequent excitation that follows after a short time interval and causes the temporarily altered concentrations of AMPA subunits in the postsynaptic membrane to be stabilized. We show that positive feedback is the crucial element in the core chemical reaction, i.e. the activation of the short-tail AMPA subunit by NEM-sensitive factor, which allows generating multiple stable equilibria. Three stable equilibria are related to LTP, LTD and a third unfixed state called ACTIVE. Our mathematical approach shows that modeling synaptic multistability is possible by making use of known substances like NMDA and AMPA receptors, NEM-sensitive factor, glutamate, CaMKII and brain-derived neurotrophic factor. Furthermore, we could show that the heteromeric combination of short- and long-tail AMPA receptor subunits fulfills the function of a memory tag.

Long-term synaptic potentiation in the superior cervical ganglion.

Brief tetanic stimulation of the preganglionic nerves to the superior cervical ganglion enhances the postganglionic response to single preganglionic stimuli for 1 to 3 hours. This long-term potentiation of transmission through the ganglion is apparently not attributable to a persistent muscarinic action of the preganglionic neurotransmitter, acetylcholine, since neither the magnitude nor the time course of the phenomenon is reduced by atropine. The decay of long-term potentiation can be described by a first-order kinetic process with a mean time constant of 80 minutes. We conclude that long-term potentiation, once considered a unique property of the hippocampus, is in fact a more general feature of synaptic function. This form of synaptic memory may significantly influence information processing and control in other regions of the nervous system, including autonomic ganglia.