What is the name for the process that strengthens the connection between two neurons in a long lasting way?

Long-Term Potentiation, Synaptic Tagging, and the Consolidation Model of Memory

The consolidation hypothesis of memory was first proposed by Müller and Pilzecker in 1900.157 They noted that memory for new information could be disrupted by learning other information shortly after the initial training. This effect, calledretroactive interference, is temporally graded such that the susceptibility of the memory is greatest immediately after learning and decreases with time. Müller and Pilzecker proposed that the memory trace must initially exist in a fragile state, but subsequently becomes stable through the process ofconsolidation. The consolidation hypothesis remains the framework for understanding the temporal course of memory processes and behavior.

For a memory trace to be consolidated, it must of course be created. The term used to describe this process isencoding. Encoding implies that the networks mediating the neural representation of an event as it is experienced do not immediately return to their previous state and are modified in such a way that potentiates reactivation of that representation. Thesynaptic plasticity and memory hypothesis states that activity-induced synaptic plasticity is both necessary and sufficient for the information storage underlying memory,158 and within this framework encoding implies that some form of synaptic plasticity has been initiated. However, encoding cannot in itself assure the propagation of a memory trace. Encoding creates the potential for the formation of a long-term memory.

The minimal events that constitute the neural correlates of encoding are incompletely understood. Cellular models demonstrate that functional changes in synaptic strength can occur in the absence of any structural change in dendritic spines.159 The perpetuation of these initial changes through structural and functional remodeling represents the neural correlate of memory consolidation. The prevailing cellular model for this is LTP,160 which describes a durable increase in synaptic transmission efficiency following a stimulation protocol. It is now recognized that LTP occurs richly throughout the hippocampus, as well as in other afferent pathways.161 LTP can be induced by nonphysiologic high-frequency stimulation, but also by stimulation protocols that resemble physiologic activity, the most important being bursts in the theta range (4-8 Hz).162 This is of notable relevance to memory, as synchronized hippocampal theta oscillations appear critical to successful memory behaviors.134

The breadth and depth of literature on the mechanisms of LTP are far too voluminous to summarize here. Nonetheless, certain principles are essential and relevant to anesthesia studies and can be stated succinctly. The induction of most forms of LTP requires activation of postsynapticN-methyl-D-aspartate (NMDA) receptors,163followed by influx of Na+ and Ca2+. This rise in intracellular Ca2+ is the critical trigger for LTP. Calcium-calmodulin-dependent kinase II (CaMKII) is then activated and autophosphorylated,164,165 leading to cytoskeletal reconfiguration.166 Activation of several other cell-signaling cascades also contribute to LTP. The terminal expression of LTP is protein synthesis, occurring in both the soma and local dendrites, and resulting in enduring structural changes at the synapse.167 Protein synthesis inhibitors have been demonstrated to consistently prevent sustained LTP in vitro and learning in vivo.168

5 LTP and Learning and Memory

LTP is the most widely proposed mechanism of memory storage in the hippocampus and neocortex. Although this issue is still debated, evidence supporting this hypothesis comes from a variety of experimental data and theoretical models (Baudry and Davis 1996). LTP is prevalent in hippocampal and cortical networks and exhibits many properties required for a large capacity information storage device: rapid induction, associativity, long duration, links with brain rhythms (in particular, the theta rhythm). Pharmacological manipulations or gene mutations interfering with LTP also interfere with various forms of learning and memory, while pharmacological agents facilitating LTP formation also facilitate learning. Finally, incorporating LTP-based rules in biologically realistic neuronal networks produces large capacity storage devices.

Drug-Induced Long-Term Potentiation in Nociceptive Pathways

In addition to postinjury forms of hyperalgesia, drug-induced forms are also of considerable clinical relevance. For example, hyperalgesia may develop in human subjects and in experimental animals during the continuous use of opioids (Chen et al 2009a) or after abrupt withdrawal of opioids (Angst et al 2003). Opioids acutely depress synaptic strength at C fibers, mainly by pre-synaptic inhibition via interference with N- and P/Q-type voltage-gated calcium channels (VGCCs) (Heinke et al 2011). Acute depression of release of neurotransmitters from nociceptive afferents is a major mechanism underlying opioid analgesia. On abrupt withdrawal from opioids (remifentanil, fentanyl, or morphine), synaptic strength not only returns to normal but also may become potentiated for prolonged periods (Drdla et al 2009,Heinl et al 2011). Induction of this opioid withdrawal LTP is post-synaptic in nature because it requires activation of post-synaptic G proteins and post-synaptic NMDA receptors and a rise in post-synaptic Ca2+ concentration. It is presently unknown whether LTP also develops during the prolonged application of opioids. The signaling pathways for activity-dependent forms of LTP and opioid withdrawal LTP largely overlap both each other and opioid-induced hyperalgesia. Whereas induction of activity-dependent and opioid withdrawal LTP requires post-synaptic signaling (Ikeda et al 2003, 2006;Drdla et al 2009), consolidation and maintenance of LTP may involve pre-synaptic mechanisms (Heinl et al 2011,Luo et al 2012).

Additional mechanisms, including descending facilitation from brain stem sites, clearly also play a role in opioid-induced hyperalgesia (Chang et al 2007,Vera-Portocarrero et al 2007,Heinl et al 2011). (See also the section entitledPlasticity in Descending Pathways, later.)

Drugs other than opioids can likewise induce LTP in nociceptive pathways when applied directly onto the spinal cord in vivo. Such substances include ATP, BDNF, the dopamine receptor D1/D5 agonist SKF 38393, and the protein kinase A (PKA) activator 8-Br-cyclic adenosine monophosphate (cAMP). In spinalized animals (i.e., when the descending inhibitory pathways are blocked), spinal application of NMDA, substance P, or neurokinin A also induces LTP at C-fiber synapses, whereas TNF-α is effective in neuropathic animals only. For review and references, see the review byRuscheweyh and associates (2011).

LTP at the synaptic relay between nociceptive nerve fibers and potential principal pain neurons in the superficial spinal dorsal horn shares induction protocols, pharmacological profiles, and signaling pathways with various forms of hyperalgesia and allodynia. LTP is thus considered a synaptic mechanism of pain amplification (Sandkühler 2009,Ruscheweyh et al 2011). It is quite likely that similar forms of plasticity exist at synapses upstream in nociceptive pathways, including synapses in the cerebral cortex (Li et al 2010,Zhuo 2011).

Critical Periods for LTP and LTD during Development

LTP and LTD are often most robust, or entirely restricted to, specific critical periods of development. In sensory cortex, these critical periods for NMDA receptor-dependent LTP and LTD occur in the first postnatal weeks, and overlap with critical periods for experience-dependent plasticity of visual and somatosensory maps, suggesting that LTP and LTD may contribute to map plasticity (Figure 3). Why LTP and LTD are restricted to these early critical periods is not known. The developmental switch in NMDA receptor subunits, which coincides with the end of critical periods in some systems, does not seem to be the causative factor, because interference with this subunit switch in transgenic mice does not alter the critical period for LTP or experience-dependent plasticity. Another hypothesis, still unproven, is that GABAergic inhibition, which increases strongly during this same developmental period, prevents effective LTP induction.

Long-Term Potentiation

Activation of NK1Rs results in the depolarization of neonatal dorsal horn neurons (Miletic and Randic 1981) and contributes to the C-fiber–evoked long-duration ventral root potential (VRP) observed in the neonatal spinal cord, an effect that diminishes after P11 (Gibbs and Kendig 1992). NK1Rs also mediate synaptic plasticity in the developing dorsal horn inasmuch as the selective NK1R antagonist L-703,606 blocked C-fiber–evoked long-term potentiation (LTP) in lamina I projection neurons from juvenile rats (Ikeda et al 2003).

Like most areas of the CNS, glutamatergic synapses in the immature dorsal horn are capable of significant activity-dependent plasticity. mGluRs are likely to exert a complex influence on synaptic plasticity in the neonatal SDH, depending on both the receptor subtype and the functional class of primary afferent input. Activation of group I mGluRs (mGluR1 and 5) results in long-term depression (LTD) of Aδ-fiber synaptic input to the SDH of young rats (Chen and Sandkuhler 2000), although LTP of C-fiber–evoked responses following high-frequency stimulation is also dependent on group I mGluRs (Azkue et al 2003). Meanwhile, it is very clear that NMDARs are essential for short-term plasticity in the neonatal spinal cord since NMDAR antagonists prevent the generation of AP “wind-up,” as well as LTP, following repetitive C-fiber stimulation in vitro (Thompson et al 1992,Randic et al 1993). Although LTP within lamina I appears to be restricted to projection neurons expressing the SP receptor NK1 at P18–P24 (Ikeda et al 2003), it remains unclear which functional subtypes of SDH neurons can generate LTP at early postnatal ages. It is also unknown whether the cellular mechanisms underlying these alterations in synaptic efficacy are developmentally regulated, as has been reported previously in the hippocampus (Yasuda et al 2003).

Relatively little is known about activity-dependent plasticity at inhibitory synapses within the developing SDH. Recent work has demonstrated that repetitive stimulation of GABAergic input to lamina II neurons results in a similar amount of short-term depression (STD) throughout the first 3 postnatal weeks, although recovery from STD occurred at a slower rate at P3 than at P21 (Ingram et al 2008). In neonates, an immature Cl− extrusion capacity can result in accumulation of intracellular Cl− during high-frequency stimulation, which also compromises the strength of synaptic inhibition by progressively reducing the Cl− driving force through GABAARs (Cordero-Erausquin et al 2005). In contrast, release of GABA and glycine within the immature SDH can be enhanced by the presynaptic actions of BDNF (Bardoni et al 2007), ATP (Jang et al 2001), or cyclic adenosine monophosphate (cAMP)–protein kinase A (PKA) signaling (Choi et al 2009).

Amylyin receptor involved in hippocampal long-term potentiation

Long-term potentiation (LTP) is a process involving persistent strengthening of synapses that leads to a long-lasting increase in signal transmission between neurons. It is an important process in the context of synaptic plasticity. LTP recording is widely recognized as a cellular model for the study of memory. Soluble oligomeric Aβ depresses hippocampal LTP and thus impairs glutamatergic NMDA receptor-mediated synaptic plasticity (Li et al., 2011). Both Aβ and hAmylin induced reductions in LTP at nanomolar concentrations, and the reduction can be blocked in the presence of the amylin receptor antagonist AC253 in wild-type mice (Kimura, MacTavish, Yang, Westaway, & Jhamandas, 2012). In transgenic AD mouse model (TgCRND8), LTP is chronically blunted due to elevated ambient levels of Aβ. AC253 can reverse LTP depression and restore it to levels observed in age-matched littermate control animals.

Pramlintide, the amylin analog, has also attenuated both Aβ- and hAmylin evoked LTP depression and partially restored LTP in AD mice (Kimura, MacTavish, Yang, Westaway, & Jhamandas, 2017). This discrepancy in the ability of an amylin receptor antagonist (AC253) and pramlintide to demonstrate similar effects of LTP might be explicable by biased agonism as mentioned earlier. The pramlintide could, under some conditions and at low concentrations (nM) such as used in the LTP study, act also as a functional antagonist for amylin receptor. However, further research is warranted to confirm this notion.

4.30.2.3 Brain Regions and LTP

LTP or LTP-like potentiation has been described in a great many different brain regions. For example, in the CA3 region of the hippocampus, two apparently distinct forms of LTP have been described. One of these is classical N-methyl-d-aspartate (NMDA) receptor (NMDAR)–dependent LTP (Zalutsky and Nicoll, 1990). The other, exhibited by the mossy fiber input to this region, is a form of LTP not dependent on NMDAR activation but, rather, requires activation of PKA and is possibly presynaptic in nature (Weisskopf et al., 1994). However, in this chapter we focus primarily on NMDAR-dependent LTP in the CA1 region of the hippocampus.

Having established the ground rules for our discussion, we are now ready to discuss the role of glutamate receptor trafficking in LTP. We also discuss the molecular mechanisms that may underlie this trafficking. Given the different roles played by the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor (AMPAR) and NMDAR in LTP, and because their trafficking mechanisms appear to differ, we discuss trafficking of the AMPAR and the NMDAR separately.

Long-Term Potentiation at Schaffer Collateral to CA1 Synapses

LTP at the Schaffer collateral to CA1 synapse is NMDA receptor-dependent and expressed in part via postsynaptic mechanisms. The early phase of LTP is normal in both RIM1α- and Rab3A-KO mice. However, more intense LTP induction protocols induce a longer-lasting form of plasticity that is dependent on protein synthesis (called late LTP). This late phase of LTP is deficient in RIM1α- and Rab3A-KO mice, implicating presynaptic expression in this form of LTP. Although the mechanism of this involvement remains a mystery, a requirement for presynaptic PKA activation has been suggested. Further study is warranted to confirm and extend this initial observation.

In summary, the loss of RIM1α at excitatory synapses leads to a relative decrease in neurotransmitter release and alterations in short-term and long-term plasticity. This suggests that RIM1α is a positive regulator of excitatory synaptic transmission and plasticity.

Expression Mechanisms of Mossy Fiber LTP

Long-term potentiation (LTP) was first described in the hippocampus by pioneering work from Tim Bliss and Terje Lømo in the early part of the 1970s. These seminal studies quickly led to a large and sustained effort to describe a synaptic phenomenon that is now widely believed to be a cellular correlate of memory formation. LTP at the mossy fiber to CA3 pyramidal neuron synapse was described a decade after these initial findings, and soon proved to be mechanistically distinct from LTP in the CA1 region of the hippocampus and the dentate gyrus. Several important findings about the induction of mossy fiber LTP were described in these early studies. For instance, several groups found that NMDA receptor activation, a defining characteristic of LTP at most other synapses, was not required for the induction of mossy fiber LTP. Whereas some aspects of mossy fiber LTP remain controversial, in particular the requirement of postsynaptic Ca2+ signaling for induction, other aspects, such as the expression mechanisms, are more firmly established. Several coincident lines of evidence have confirmed that mossy fiber to CA3 pyramidal neuron LTP is expressed in the presynaptic terminal as a long lasting increase in glutamate release probability. The evidence for this includes clear reductions in paired pulse ratio, increased rate of open channel block of NMDA receptors, and quantal variance analysis, which strongly supports an increase in transmitter release probability following induction of LTP.

5.04.2.6.2 Long-Term Potentiation (LTP) and Long-Term Depression (LTD)

LTP and LTD are persistent changes of synaptic strength after peripheral nerve stimulation which may last for hours up to days and months. In the hippocampus LTP is considered a fundamental cellular model of leaning and memory formation (Sandkühler, 2008). LTP and LTD can also be induced in the spinal cord (Randic et al., 1993; Rygh et al., 1999; Sandkühler and Liu, 1998; Svendsen et al., 1997). They appear as increases or decreases of field potentials in the superficial dorsal horn. The most pronounced LTP at a short latency is elicited after application of a high frequency train (50–100 Hz) of electrical stimuli that are suprathreshold for C-fibers, but also trains of low frequency stimulation (2–10 Hz) of C-fibers can induce robust LTP (Sandkühler, 2008). Importantly, LTP can also be elicited by noxious stimulation such as subcutaneous injection of capsaicin or formalin although the time course of LTP development is much slower (Sandkühler, 2008). Finally, in spinalized rats, LTP can also be evoked by topical application of NMDA, substance P, neurokinin A and others (Sandkühler, 2008). Typical examples of LTP induction are displayed in Fig. 4.

Functionally, it is thought that spinal LTP underlies hyperalgesia. After establishment of LTP, suprathreshold excitatory input will evoke stronger excitation of nociceptive neurons. Previously subthreshold excitatory input from the subliminal fringe of a neuron's receptive field may now elicit action potential firing and thus enlarge painful areas. Some spinal dorsal horn neurons may receive subthreshold input from somatotopically inappropriate body areas, e.g. the contralateral body half, thus causing mirror image or radiating pain. However, LTP does not significantly reduce pain threshold and is therefore not considered a likely mechanism of allodynia (Sandkühler, 2008).

Notably, the induction of LTP is context-sensitive. Electrical stimulation of Aδ-fibers may elicit LTD in the superficial dorsal horn. This latter form of plasticity may be a basis of inhibitory mechanisms that counteract responses to noxious stimulation (Sandkühler et al., 1997). However, under conditions of impaired inhibition, electrical stimulation of Aδ-fibers may elicit LTP. The direction of Aδ-fiber-induced effects (LTP or LTD) may be voltage-dependent (Randic et al., 1993).