scholarly journals Specific nanoscale synaptic reshuffling and control of short-term plasticity following NMDAR- and P2XR-dependent Long-Term Depression

2019 ◽  
Author(s):  
Benjamin Compans ◽  
Magalie Martineau ◽  
Remco V. Klaassen ◽  
Thomas M. Bartol ◽  
Corey Butler ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Molecular Mechanisms ◽  
Super Resolution ◽  
Long Term Potentiation ◽  
Global Changes ◽  
Short Term ◽  
Long Term Depression ◽  
Term Potentiation ◽  
And Control

Long-Term Potentiation (LTP) and Long-Term Depression (LTD) of excitatory synaptic transmission are considered as cellular basis of learning and memory. These two forms of synaptic plasticity have been mainly attributed to global changes in the number of synaptic AMPA-type glutamate receptor (AMPAR) through a regulation of the diffusion/trapping balance at the PSD, exocytosis and endocytosis. While the precise molecular mechanisms at the base of LTP have been intensively investigated, the ones involved in LTD remains elusive. Here we combined super-resolution imaging technique, electrophysiology and modeling to describe the various modifications of AMPAR nanoscale organization and their effect on synaptic transmission in response to two different LTD protocols, based on the activation of either NMDA receptors or P2X receptors. While both type of LTD are associated with a decrease in synaptic AMPAR clustering, only NMDAR-dependent LTD is associated with a reorganization of PSD-95 at the nanoscale. This change increases the pool of diffusive AMPAR improving synaptic short-term facilitation through a post-synaptic mechanism. These results demonstrate that specific dynamic reorganization of synapses at the nanoscale during specific LTD paradigm allows to improve the responsiveness of depressed synapses.

Postsynaptic Application of a cAMP Analogue Reverses Long-Term Potentiation in Hippocampal CA1 Pyramidal Neurons

2002 ◽  
Vol 87 (6) ◽  
pp. 3018-3032 ◽  
Author(s):  
Nikolai Otmakhov ◽  
John E. Lisman
Keyword(s):  
Molecular Mechanisms ◽  
Competitive Inhibition ◽  
Drug Application ◽  
Specific Effect ◽  
Long Term Potentiation ◽  
Term Potentiation ◽  
Camp Analogue ◽  
And Control ◽  
Dependent Processes

The molecular mechanisms that underlie the maintenance of long-term potentiation (LTP) remain unclear. We have examined the influence of postsynaptic cAMP-dependent processes on LTP maintenance in CA1 hippocampal cells. After LTP induction, drugs affecting cAMP-dependent processes were perfused into the cell through a patch pipette. A cAMP analogue, Rp-cAMPS (4 mM), dramatically decreased the amplitude of potentiated synaptic responses. The amplitude of responses in the control pathway was also decreased but to a lesser extent, indicating a specific effect on the potentiation process. This specific effect was not due to the larger amplitude of potentiated responses, was not use-dependent and, unlike other factors that affect LTP maintenance, did not depend on the delay (2, 10, or 25 min) of drug application after LTP induction. Lower concentrations of Rp-cAMPS (1.0 and 0.4 mM) also produced an inhibitory effect but reduced the LTP and control pathways comparably. One possible action of Rp-cAMPS is competitive inhibition of protein kinase A (PKA). Surprisingly, a potent and noncompetitive PKA inhibitor, regulatory type II subunit of PKA, produced only a weak depression of potentiated and control responses indicating there must be other targets for Rp-cAMPS. Moreover, Sp-8-OH-cAMPS, which is an activator of PKA, and Rp-8-OH-cAMPS, which is a weak inhibitor of PKA, both produced effects similar to those of Rp-cAMPS. We conclude that there are postsynaptic cyclic nucleotide-dependent processes that can specifically alter the mechanisms that maintain LTP and that are not primarily dependent on PKA.

scholarly journals Dissecting the Roles of Kalirin-7/PSD-95/GluN2B Interactions in Different Forms of Synaptic Plasticity

2020 ◽  
Author(s):  
Mason L. Yeh ◽  
Jessica R Yasko ◽  
Eric S. Levine ◽  
Betty A. Eipper ◽  
Richard Mains
Keyword(s):  
Synaptic Plasticity ◽  
Molecular Mechanisms ◽  
Long Term Potentiation ◽  
Surface Expression ◽  
Synaptic Function ◽  
Nucleotide Exchange ◽  
Long Term Depression ◽  
Term Potentiation ◽  
Knockout Animals

Abstract Background: Kalirin-7 (Kal7) is a multidomain scaffold and guanine nucleotide exchange factor localized to the postsynaptic density, where Kal7 is crucial for synaptic plasticity. Kal7 knockout mice exhibit marked suppression of long-term potentiation and long-term depression in hippocampus, cerebral cortex and spinal cord, with depressed surface expression of GluN2B receptor subunits and dramatically blunted perception of pain. Kal7 knockout animals show exaggerated locomotor responses to psychostimulants and self-administer cocaine more enthusiastically than wildtype mice. Results: To address the underlying cellular and molecular mechanisms which are deranged by loss of Kal7, we infused candidate intracellular interfering peptides to acutely challenge the synaptic function(s) of Kal7 with potential protein binding partners, to determine if plasticity deficits in Kal7-/- mice are the product of developmental processes since conception, or could be produced on a much shorter time scale. We demonstrated that these small intracellular peptides disrupted normal long-term potentiation and long-term depression, strongly suggesting that maintenance of established interactions of Kal7 with PSD-95 and/or GluN2B is crucial to synaptic plasticity. Conclusions: Blockade of the Kal7-GluN2B interaction was most effective at blocking long-term potentiation, but had no effect on long-term depression. Biochemical approaches indicated that Kal7 interacted with PSD-95 at multiple sites within Kal7.

Learning and Memory

The Neuron ◽  
2015 ◽  
pp. 489-528
Author(s):  
Irwin B. Levitan ◽  
Leonard K. Kaczmarek
Keyword(s):  
Learning And Memory ◽  
Molecular Mechanisms ◽  
Long Term Potentiation ◽  
Memory Formation ◽  
Spike Timing ◽  
Cellular Mechanisms ◽  
Long Term Depression ◽  
Nervous Systems ◽  
Term Potentiation

Psychologists have described different kinds of learning and memory, and there is an ongoing search for the physical basis of these distinctions and for the cellular and molecular mechanisms responsible. Because of the complexity of most nervous systems, the search has focused to a large extent on animals with relatively simple nervous systems and on reduced preparations. Common themes have emerged, such as the requirement for signaling pathways linked to calcium and cyclic AMP, and the fact that pathways used in normal development continue to be used for plasticity in adults. At the same time, it is clear that there is an enormous diversity of cellular mechanisms that contribute to short-term and long-term phases of memory formation. These include long-term potentiation (LTP), long-term depression (LTD), spike-timing dependent plasticity, synaptic tagging, and synaptic scaling. Each type of synaptic connection has its own personality such that, in response to a particular pattern of stimulation, one synapse may increase its postsynaptic receptors while another may expand its presynaptic terminals.

scholarly journals Metaplastic reinforcement of long-term potentiation in rat hippocampal area CA2 by cholinergic receptor activation

2020 ◽  
Author(s):  
Amrita Benoy ◽  
Mohammad Zaki Bin Ibrahim ◽  
Thomas Behnisch ◽  
Sreedharan Sajikumar
Keyword(s):  
Synaptic Transmission ◽  
Long Term Potentiation ◽  
Cholinergic Receptor ◽  
Synaptic Depression ◽  
Receptor Activation ◽  
Long Term Depression ◽  
Schaffer Collateral ◽  
Term Potentiation ◽  
Hippocampal Area

AbstractHippocampal CA2, an inconspicuously positioned area between the well-studied CA1 and CA3 subfields, has captured research interest in recent years due to its role in the formation of social memory. The effects of synaptic depression for subsequent long-term potentiation (LTP) of synaptic transmission at entorhinal cortical (EC)-CA2 and Schaffer collateral (SC)-CA2 synapses have not been previously explored. Here we show that cholinergic receptor activation with the non-selective cholinergic agonist carbachol (CCh) triggers a long-term synaptic depression (CCh-LTD) of field excitatory postsynaptic potentials at EC- and SC-CA2 synapses in the hippocampus of adult rats. The activation of muscarinic acetylcholine receptors (mAChRs) is critical for the induction of an early phase (<100 min) of CCh-LTD, with a strong dependency upon M3 mAChR activation and a weaker one by M1 mAChRs. Interestingly, muscarinic M2 and nicotinic receptor activation are crucially involved in the late phase (>100 min) of CCh-LTD. Importantly, CCh priming lowers the threshold, in a protein synthesis-dependent manner, for the late maintenance of LTP that can be subsequently induced by high-frequency electrical stimulation at EC- or SC-CA2 pathways. The results demonstrate that CA2 synaptic learning rules are modified in a metaplastic manner, wherein synaptic modifications triggered by cholinergic stimulation can dictate the outcome of future plasticity events. Moreover, the observed enabling of late LTP at EC inputs to CA2 following the priming stimulus co-exists with concurrent sustained CCh-LTD at SC-CA2 and is dynamically scaled by modulation of SC-CA2 synaptic transmission.Significance StatementThe release of the neuromodulator acetylcholine is critically involved in processes of hippocampus-dependent memory formation. Cholinergic afferents originating in the medial septum and diagonal bands of Broca terminating in the hippocampal area CA2 might play an important role in the modulation of area-specific synaptic plasticity. Our findings demonstrate that cholinergic receptor activation induces a long-term depression of synaptic transmission at entorhinal cortical- and Schaffer collateral-CA2 synapses. This cholinergic activation-mediated long-term depression displays a bidirectional metaplastic switch to long-term potentiation on a future timescale. This suggests that such bidirectional synaptic modifications triggered by the dynamic modulation of tonic cholinergic receptor activation may support the formation of CA2-dependent memories given the increased hippocampal cholinergic tone during active wakefulness observed in exploratory behaviour.

Distinct Transmitter Release Properties Determine Differences in Short-Term Plasticity at Functional and Silent Synapses

2006 ◽  
Vol 95 (5) ◽  
pp. 3024-3034 ◽  
Author(s):  
Carolina Cabezas ◽  
Washington Buño
Keyword(s):  
Transmitter Release ◽  
Molecular Mechanisms ◽  
Long Term Potentiation ◽  
Lower Percentage ◽  
Functional Importance ◽  
Short Term ◽  
Short Term Plasticity ◽  
Silent Synapses ◽  
Term Potentiation

Recent evidence suggests that functional and silent synapses are not only postsynaptically different but also presynaptically distinct. The presynaptic differences may be of functional importance in memory formation because a proposed mechanism for long-term potentiation is the conversion of silent synapses into functional ones. However, there is little direct experimentally evidence of these differences. We have investigated the transmitter release properties of functional and silent Schaffer collateral synapses and show that on the average functional synapses displayed a lower percentage of failures and higher excitatory postsynaptic current (EPSC) amplitudes than silent synapses at +60 mV. Moreover, functional but not silent synapses show paired-pulse facilitation (PPF) at +60 mV and thus presynaptic short-term plasticity will be distinct in the two types of synapse. We examined whether intraterminal endoplasmic reticulum Ca2+ stores influenced the release properties of these synapses. Ryanodine (100 μM) and thapsigargin (1 μM) increased the percentage of failures and decreased both the EPSC amplitude and PPF in functional synapses. Caffeine (10 mM) had the opposite effects. In contrast, silent synapses were insensitive to both ryanodine and caffeine. Hence we have identified differences in the release properties of functional and silent synapses, suggesting that synaptic terminals of functional synapses express regulatory molecular mechanisms that are absent in silent synapses.

Sign in / Sign up

Export Citation Format

Share Document