Synaptic Tagging during Synapse-Specific Long-Term Facilitation of Aplysia Sensory-Motor Neurons

Synaptic plasticity can last from a fraction of a second to weeks depending on how it was induced. The mechanisms that underlie short-, intermediate-, and long-term plasticity have been intensively studied at central synapses of both vertebrates and invertebrates; however, peripheral plasticity has not received as much attention. In this study, we investigated the mechanisms that contribute to a persistent form of plasticity at neuromuscular synapses in buccal muscle I3a of Aplysia.These synapses are reversibly facilitated by the small cardioactive peptide (SCP), a peptide cotransmitter that is intrinsic to the motor neurons, and persistently facilitated by serotonin (5HT) released from modulatory neurons that are extrinsic to the motor circuit. Many of the short-term effects of 5HT and SCP are mediated by the cAMP pathway, but little is known about the mechanisms that underlie persistent modulation. We were able to eliminate several possible mechanisms. One of these was the possibility that the apparent reversal of SCP's effects was due to desensitization of the SCP receptor. Superfusion for longer periods or with higher concentrations of SCP indicate that the SCP receptors do not desensitize. We also determined that new protein synthesis is not required for the persistent facilitation of EJPs. Another possibility was that 5HT was taken up and slowly re-released. Our results suggest that this mechanism is also unlikely. Activation of the cAMP pathway does not appear to mediate persistent effects; however, 5HT as well as SCP does cause persistent increases in cAMP levels that can prime I3a synapses and increase the effectiveness of activators of the cAMP pathway. Instead, the persistent effects of 5HT are mimicked by phorbol, suggesting that protein kinase C or an Aplysia homologue of unc13 may mediate these effects. These results, in combination with results from experiments on the sensory neurons that contribute to withdrawal reflexes in Aplysia, suggest that the mechanisms for intermediate- and long-term facilitation may reside in all of the synapses involved in the sensory to motor response reflex.

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Long-term sensitization training in Aplysia leads to an increase in the expression of BiP, the major protein chaperon of the ER.

The Journal of Cell Biology ◽

10.1083/jcb.119.5.1069 ◽

1992 ◽

Vol 119 (5) ◽

pp. 1069-1076 ◽

Cited By ~ 56

Author(s):

D Kuhl ◽

T E Kennedy ◽

A Barzilai ◽

E R Kandel

Keyword(s):

Protein Synthesis ◽

Motor Neurons ◽

Structural Changes ◽

State Level ◽

Long Term Memory ◽

Major Protein ◽

Synaptic Connections ◽

Term Memory ◽

Long Term Facilitation

Long-term memory for sensitization of the gill- and siphon-withdrawal reflexes in Aplysia californica requires RNA and protein synthesis. These long-term behavioral changes are accompanied by long-term facilitation of the synaptic connections between the gill and siphon sensory and motor neurons, which are similarly dependent on transcription and translation. In addition to showing an increase in over-all protein synthesis, long-term facilitation is associated with changes in the expression of specific early, intermediate, and late proteins, and with the growth of new synaptic connections between the sensory and motor neurons of the reflex. We previously focused on early proteins and have identified four proteins as members of the immunoglobulin family of cell adhesion molecules related to NCAM and fasciclin II. We have now cloned the cDNA corresponding to one of the late proteins, and identified it as the Aplysia homolog of BiP, an ER resident protein involved in the folding and assembly of secretory and membrane proteins. Behavioral training increases the steady-state level of BiP mRNA in the sensory neurons. The increase in the synthesis of BiP protein is first detected 3 h after the onset of facilitation, when the increase in overall protein synthesis reaches its peak and the formation of new synaptic terminals becomes apparent. These findings suggest that the chaperon function of BiP might serve to fold proteins and assemble protein complexes necessary for the structural changes characteristic of long-term memory.

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TGF-β1 in Aplysia: Role in Long-Term Changes in the Excitability of Sensory Neurons and Distribution of TβR-II-Like Immunoreactivity

Learning & Memory ◽

10.1101/lm.6.3.317 ◽

1999 ◽

Vol 6 (3) ◽

pp. 317-330

Author(s):

Jeannie Chin ◽

Annie Angers ◽

Leonard J. Cleary ◽

Arnold Eskin ◽

John H. Byrne

Keyword(s):

Synaptic Plasticity ◽

Sensory Neurons ◽

Motor Neurons ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Tissue Extracts ◽

The Central Nervous System ◽

Long Term Facilitation ◽

Tgf Β1

Exogenous recombinant human transforming growth factor β-1 (TGF-β1) induced long-term facilitation ofAplysia sensory-motor synapses. In addition, 5-HT-induced facilitation was blocked by application of a soluble fragment of the extracellular portion of the TGF-β1 type II receptor (TβR-II), which presumably acted by scavenging an endogenous TGF-β1-like molecule. Because TβR-II is essential for transmembrane signaling by TGF-β, we sought to determine whether Aplysia tissues contained TβR-II and specifically, whether neurons expressed the receptor. Western blot analysis of Aplysia tissue extracts demonstrated the presence of a TβR-II-immunoreactive protein in several tissue types. The expression and distribution of TβR-II-immunoreactive proteins in the central nervous system was examined by immunohistochemistry to elucidate sites that may be responsive to TGF-β1 and thus may play a role in synaptic plasticity. Sensory neurons in the ventral–caudal cluster of the pleural ganglion were immunoreactive for TβR-II, as well as many neurons in the pedal, abdominal, buccal, and cerebral ganglia. Sensory neurons cultured in isolation and cocultured sensory and motor neurons were also immunoreactive. TGF-β1 affected the biophysical properties of cultured sensory neurons, inducing an increase of excitability that persisted for at least 48 hr. Furthermore, exposure to TGF-β1 resulted in a reduction in the firing threshold of sensory neurons. These results provide further support for the hypothesis that TGF-β1 plays a role in long-term synaptic plasticity in Aplysia.

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Neural analogue of long-term sensitization training produces long-term (24 and 48 h) facilitation of the sensory-to-motor neuron connection in Aplysia

Journal of Neurophysiology ◽

10.1152/jn.1994.72.2.778 ◽

1994 ◽

Vol 72 (2) ◽

pp. 778-784 ◽

Cited By ~ 10

Author(s):

F. Zhang ◽

J. R. Goldsmith ◽

J. H. Byrne

Keyword(s):

Sensory Neurons ◽

Motor Neurons ◽

Peripheral Nerves ◽

Time Course ◽

Membrane Properties ◽

Four Blocks ◽

Long Term Facilitation ◽

Stimulation Of Nerve ◽

Stimulation Of

1. An in vitro analogue of long-term sensitization training was used to gain insights into the mechanisms and time course of the memory for long-term sensitization in Aplysia. The analogue, consisting of four blocks of shocks, was delivered to peripheral nerves of the isolated pleural-pedal ganglia, which contain the sensory neurons and motor neurons that mediate the tail withdrawal reflex. 2. Long-term facilitation of the connections between the sensory neurons and motor neurons was produced by the conjoint stimulation of two peripheral nerves, P8 and P9. Long-term facilitation, however, was not observed after conjoint stimulation of three nerves, P7, P8, and P9. 3. The preparation was viable and stable (no changes in the amplitudes of excitatory postsynaptic potentials (EPSPs) and membrane properties in controls) for at least 48 h. Moreover, the long-term facilitation persisted for at least 48 h. 4. We observed no significant long-term changes in the resting membrane potentials of the sensory and motor neurons or in the input resistance of the motor neurons 24 and 48 h after the conjoint stimulation of nerves P8 and P9. Thus changes in these biophysical properties do not appear to contribute to the expression of long-term facilitation. 5. The finding that conjoint stimulation of three nerves, P7, P8, and P9, produced no long-term facilitation raised the possibility that stimulation of nerve P7 alone might produce long-term inhibition that opposes the facilitatory effects induced by conjoint stimulation of nerves P8 and P9. Stimulation of nerve P7 alone, however, had no long-term inhibitory effect on the EPSPs.(ABSTRACT TRUNCATED AT 250 WORDS)

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Reinstatement of long-term memory following erasure of its behavioral and synaptic expression in Aplysia

eLife ◽

10.7554/elife.03896 ◽

2014 ◽

Vol 3 ◽

Cited By ~ 76

Author(s):

Shanping Chen ◽

Diancai Cai ◽

Kaycey Pearce ◽

Philip Y-W Sun ◽

Adam C Roberts ◽

...

Keyword(s):

Motor Neurons ◽

Long Term Memory ◽

Synaptic Connections ◽

Synaptic Growth ◽

Term Memory ◽

Synaptic Structure ◽

Synaptic Change ◽

Long Term Facilitation ◽

The Brain

Long-term memory (LTM) is believed to be stored in the brain as changes in synaptic connections. Here, we show that LTM storage and synaptic change can be dissociated. Cocultures of Aplysia sensory and motor neurons were trained with spaced pulses of serotonin, which induces long-term facilitation. Serotonin (5HT) triggered growth of new presynaptic varicosities, a synaptic mechanism of long-term sensitization. Following 5HT training, two antimnemonic treatments—reconsolidation blockade and inhibition of PKM—caused the number of presynaptic varicosities to revert to the original, pretraining value. Surprisingly, the final synaptic structure was not achieved by targeted retraction of the 5HT-induced varicosities but, rather, by an apparently arbitrary retraction of both 5HT-induced and original synapses. In addition, we find evidence that the LTM for sensitization persists covertly after its apparent elimination by the same antimnemonic treatments that erase learning-related synaptic growth. These results challenge the idea that stable synapses store long-term memories.

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Baseline Arterial CO2 Pressure Regulates Acute Intermittent Hypoxia-Induced Phrenic Long-Term Facilitation in Rats

Frontiers in Physiology ◽

10.3389/fphys.2021.573385 ◽

2021 ◽

Vol 12 ◽

Author(s):

Raphael R. Perim ◽

Mohamed El-Chami ◽

Elisa J. Gonzalez-Rothi ◽

Gordon S. Mitchell

Keyword(s):

Motor Neurons ◽

Intermittent Hypoxia ◽

Progressive Increase ◽

Serotonin Release ◽

Serotonergic Neurons ◽

Burst Amplitude ◽

Experimental Protocols ◽

End Tidal ◽

Long Term Facilitation

Moderate acute intermittent hypoxia (mAIH) elicits a progressive increase in phrenic motor output lasting hours post-mAIH, a form of respiratory motor plasticity known as phrenic long-term facilitation (pLTF). mAIH-induced pLTF is initiated by activation of spinally-projecting raphe serotonergic neurons during hypoxia and subsequent serotonin release near phrenic motor neurons. Since raphe serotonergic neurons are also sensitive to pH and CO2, the prevailing arterial CO2 pressure (PaCO2) may modulate their activity (and serotonin release) during hypoxic episodes. Thus, we hypothesized that changes in background PaCO2 directly influence the magnitude of mAIH-induced pLTF. mAIH-induced pLTF was evaluated in anesthetized, vagotomized, paralyzed and ventilated rats, with end-tidal CO2 (i.e., a PaCO2 surrogate) maintained at: (1) ≤39 mmHg (hypocapnia); (2) ∼41 mmHg (normocapnia); or (3) ≥48 mmHg (hypercapnia) throughout experimental protocols. Although baseline phrenic nerve activity tended to be lower in hypocapnia, short-term hypoxic phrenic response, i.e., burst amplitude (Δ = 5.1 ± 1.1 μV) and frequency responses (Δ = 21 ± 4 bpm), was greater than in normocapnic (Δ = 3.6 ± 0.6 μV and 8 ± 4, respectively) or hypercapnic rats (Δ = 2.0 ± 0.6 μV and −2 ± 2, respectively), followed by a progressive increase in phrenic burst amplitude (i.e., pLTF) for at least 60 min post mAIH. pLTF in the hypocapnic group (Δ = 4.9 ± 0.6 μV) was significantly greater than in normocapnic (Δ = 2.8 ± 0.7 μV) or hypercapnic rats (Δ = 1.7 ± 0.4 μV). In contrast, although hypercapnic rats also exhibited significant pLTF, it was attenuated versus hypocapnic rats. When pLTF was expressed as percent change from maximal chemoreflex stimulation, all pairwise comparisons were found to be statistically significant (p < 0.05). We conclude that elevated PaCO2 undermines mAIH-induced pLTF in anesthetized rats. These findings contrast with well-documented effects of PaCO2 on ventilatory LTF in awake humans.

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