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Jiang, F.; Bello, S.T.; Gao, Q.; Lai, Y.; Li, X.; He, L. Long-Term Potentiation Mechanisms of Excitatory and Inhibitory Synapses. Encyclopedia. Available online: https://encyclopedia.pub/entry/43172 (accessed on 14 June 2024).
Jiang F, Bello ST, Gao Q, Lai Y, Li X, He L. Long-Term Potentiation Mechanisms of Excitatory and Inhibitory Synapses. Encyclopedia. Available at: https://encyclopedia.pub/entry/43172. Accessed June 14, 2024.
Jiang, Feixu, Stephen Temitayo Bello, Qianqian Gao, Yuanying Lai, Xiao Li, Ling He. "Long-Term Potentiation Mechanisms of Excitatory and Inhibitory Synapses" Encyclopedia, https://encyclopedia.pub/entry/43172 (accessed June 14, 2024).
Jiang, F., Bello, S.T., Gao, Q., Lai, Y., Li, X., & He, L. (2023, April 18). Long-Term Potentiation Mechanisms of Excitatory and Inhibitory Synapses. In Encyclopedia. https://encyclopedia.pub/entry/43172
Jiang, Feixu, et al. "Long-Term Potentiation Mechanisms of Excitatory and Inhibitory Synapses." Encyclopedia. Web. 18 April, 2023.
Long-Term Potentiation Mechanisms of Excitatory and Inhibitory Synapses
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Neuronal and glial cells are the main components of the brain. Approximately 50% of the brain is neuronal cells; the other half is glial cells, which all play an important role in the mammalian brain. Billions of neurons are connected and communicate via synapses inextricably linked to behavior, memory, and neurological diseases. Synaptic plasticity is a change in neural connection strength that occurs in response to activity. Reorganization of the structural and functional connections of synapses occurs in response to internal or external stimuli, leading to the strengthening or weakening of synaptic connections via synaptic plasticity. Long-term potentiation (LTP) has been widely used as an ideal model for studying synaptic plasticity, learning, and memory.
LTP iLTP electrophysiological experiments

1. Introduction

Consistent increases in neurotransmitter release result in omnipresent forms of LTP [1]. Plenty of evidence suggests that neuronal activity can trigger sustained increases in neurotransmitter release at excitatory and inhibitory synapses, leading to LTP. The use of intracellular and patch-clamp recordings revealed various interesting mechanisms that trigger inhibitory synaptic LTP in different brain areas, indicating that iLTP may be associated with various phenomena. The expression of iLTP is induced by the release of the neurotransmitter GABA, which is exhibited by inhibitory synapses throughout the central nervous system (CNS) and can dynamically control information flow in neural circuits [2]. Understanding various mechanisms that induce GABA release is beneficial for understanding the balance between GABA excitation and inhibition.

2. Nitric Oxide (NO)

NO is a kind of endothelium-derived relaxing factor [3], which is synthesized by NO synthase (calcium/calmodulin-dependent) with L-arginine as substrate [4]. Ca2+/calmodulin regulates constitutive expression types of the NOS family [5], confirming a possible connection to LTP and iLTP induction. Meanwhile, behavioral studies show that the NO/cGMP plays a role in learning and memory [6][7] because NO donors, l-Arginine, or cGMP analogs enhanced memory, whereas NOS inhibitors or genetic deletion hampered various types of memory [6].
It has been reported that, as one of the retrograde signals to maintain iLTP in GABAergic synapses in the VTA, NO first requires glutamate to activate the NMDA receptor, which increases postsynaptic calcium concentration. As a result, NO is released as a retrograde signal by NO synthase and also initiates sustained enhancement to increase cGMP levels to boost GABA release, which puts brain slices into use with NO scavengers (Mu-opioid receptors) to inhibit NO production. Single exposures to cocaine and nicotine and acute stress blocked NO-iLTP [8][9]. A combination of HFS and whole-cell recordings induced and recorded iLTP. iLTP is associated with modifying the coefficient of variation and the paired-pulse ratio of induced GABAA receptors. Furthermore, IPSCs are suggested to be maintained by a sustained increase in GABA release [8].
Similarly, in a series of hippocampal neuron (CA1 and CA3) experiments [10][11][12], it was proved that NO could activate soluble guanylate cyclase (sGC), which can catalyze the conversion of GTP into cGMP after activation, increasing the level of cGMP, thereby activating cGMP-dependent protein kinase (PKG) [13]. Following that, various proteases and phosphodiesterases exert their effects to increase the release of transmitters [14][15].
As required, NO is synthesized in the cell and dendrites rather than stored in synaptic vesicles, making NO-mediated transmission different from classical forms of neurotransmission. The biological properties of NO as a gaseous molecule allow it to freely permeate biomembranes and diffuse rapidly to control synaptic transmission and plasticity.

3. BDNF-TrkB

Brain-derived neurotrophic factor (BDNF) is a protein that promotes nerve growth activity, can regulate excitatory and inhibitory transmission [1], and significantly influences the development of CNS neurons. Part of the BNDF receptors belongs to the tyrosine-related receptor kinase family (Trk), among which TrkB has the highest affinity with BDNF and is the primary functional receptor of BDNF [16]. This neurotrophin regulates synaptic function in the hippocampus by modulating presynaptic transmitter release or enhancing postsynaptic transmitter sensitivity [17]. BDNF signaling plays a role in the pathogenesis of several important diseases, including Alzheimer’s disease (AD) [18], depression, schizophrenia, and anxiety disorders [17]. Modulation of BDNF pathways could, therefore, offer a feasible strategy to treat various neurological disorders.
Gubelini et al. combined pharmacology and whole-cell recording to prove that retrograde BDNF can enhance the inhibitory function [19], whereas TrkB conductivity inhibitors do not block the inhibitory function. Induction of iLTP requires elevated postsynaptic calcium, and intracellular calcium promotes BNDF release/secretion [20]. However, different evidence indicated whether BDNF is required for LTP by combining two-photon imaging: the types of LTP at Schaffer collateral synapses selectively required BDNF. According to these findings, different presynaptic and postsynaptic modules exhibit long-term plasticity [21]. The activation of presynaptic plasticity modules, but not postsynaptic modules, depends on BDNF release from CA3 neurons. Presynaptic neurons provide BDNF, and this type of LTP requires L-type voltage-gated Ca2+ channel activation [21]. There is also evidence that hippocampus volume has an association with BDNF-TrkB signaling [22][23].

4. NMDAR-Dependent

NMDAR is an ion channel receptor with high calcium permeability, which can regulate neuronal activity through different neurotransmitters [24]. The key mechanism by which NMDARs participate in postsynaptic LTP induction is voltage dependence. In order to activate postsynaptic NMDARs, two conditions need to occur simultaneously. First, glutamate needs to be released and bound with the help of postsynaptic NMDARs; second, the postsynaptic membrane needs to be depolarized to remove the block of extracellular Mg2+. Thus, calcium influx enters the postsynaptic cell from the extracellular space through the open NMDARs, which then activates a series of signaling molecules in the postsynaptic cell, including calmodulin (CaM), protein kinase A (PKA), cyclic AMP (cAMP), immediate early genes, and enzymes that produce diffusible retrograde messengers [25]. iLTP is also present in GABAergic stellate cells (SC inhibitory synapses), and, as with LTP in excitatory synapses, it requires GABAergic terminals to activate NMDAR [26][27][28]. Stimulation with glutamatergic inputs (parallel fibers) with similar physiological activity patterns triggered a sustained increase in GABA release from stellate cells using whole-cell recordings. Moreover, in combination with extracellular recordings, enhanced inhibitory transmission reduced the firing frequency and altered the pattern of action potential activity in stellate cells. Induction of sustained increases in GABA release requires activation of NMDA receptors, and pharmacological and genetic approaches have identified presynaptic cAMP/protein kinase A (PKA) signaling and the active zone protein RIM1α as key pathways required for sustained enhancement of GABA release. Thus, a common mechanism underlies the presynaptic plasticity of excitatory and inhibitory transmissions.
Inhibitory synaptic plasticity, triggered by short- and high-frequency inhibition of the postsynaptic electrical activity of GABAergic transmission, is essentially due to an increase in postsynaptic intracellular calcium [29]. Intracellular calcium can be altered postsynaptically by various mechanisms (e.g., PKC, CaMKII, Src, and PKA [30]). These protein kinases have dual roles in LTP formation and maintenance. On the one hand, calcium ions can immediately activate them and contribute to LTP induction. On the other hand, they have an autophosphorylation function. However, the modular process for long-term potentiation induction is extremely complex and has not been completely understood yet. Future experiments using whole-cell recordings in combination with pharmacology and genetics will provide a more thorough understanding soon.
Excitatory synapses produced homosynaptic and heterosynaptic LTP. Contrarily, iLTP mechanisms are heterosynaptic in nature, which can be induced by episodes of strong postsynaptic activity during which synapses are inactive, thereby directing any synapses that are irrelevant to heterosynaptic changes [31], and have the final goal of stimulating GABA to release into the GABAAR, which allows inhibitory interneurons to counteract prominent excitation and restrict neuronal activity transmission to control the output of the target neuron. It is worth mentioning that, since no synaptic stimulation is involved in the induction process due to the intracellular photolytic release of caged calcium ions and tonicity, LTP can be regarded as heterosynaptic.
In addition, as membrane clamp recordings are programmed to record synaptic functions, studying slices from inhibitory neurons or immature animals is becoming more common.

5. Glial Cells

Connecting neurons and glial cells are essential for neuroplasticity [32]. Growing evidence suggests that astrocytes are crucial for excitatory and inhibiting signaling [33]. Furthermore, gliotransmitters released by astrocytes, including ATP [32][34], D-serine [35][36], and adenosine [37], are necessary for NMDA-dependent LTP.
Importantly, glia, particularly astrocytes, bidirectionally communicate dynamically with neurons following information processing, neuronal activity, and behavior [38]. Briefly, astrocytes respond to neuronal activity and neurotransmitters by activating metabotropic receptors and releasing the gliotransmitters, which feed back to neurons [39][40]. The ATP released by astrocytes modulates synaptic transmission directly or through its metabolic product adenosine and can activate neuronal P2 receptors, P2X, and P2Y, which regulate synaptic homeostasis and plasticity [34][39]. In 2018, Adamsky et al. showed that activating astrocytic in CA1 induced LTP formation [41]. Furthermore, Stevens et al. demonstrated earliest that glial cells regulate neuronal activity by secreting D-serine [42]. Later, D-serine released from astrocytes, Ca2+-dependent, has been reported as closely related to LTP formation through modulating NMDA receptor function [35].  LTP formation could be blocked by clamping internal Ca2+ in individual CA1 astrocytes, and the blockade could be reversed by exogenous D-serine application [35]. Astrocyte–neuron communication was also related to synergism between vesicular and non-vesicular gliotransmission. Cortical astrocytes can release gliotransmitters, glutamate, and D-serine by combining SNARE-dependent exocytosis and non-vesicular mechanisms dependent on TREK-1 and Best1 channels, strongly affecting the glia-driven regulation of synaptic plasticity in hippocampus and neocortex [43]. Astrocytes have numerous large pore links. Molecular communication can travel a long distance. Neurons are divided from each other by the aquatic cleft of synapses and thus cannot interact directly with each other except through chemical communication [44]. However, astrocytes communicate extensively via large pores known as gap junctions, which may propagate molecular signaling to a long distance [45]. Moreover, this communication is enforced by polyamine spermine [44][45]. Polyamines, such as putrescine and spermine, are also gliotransmitters [33].
Putrescine and produced from putrescine GABA: some evidence pointing to an interesting mechanism. A type of gliotransmitters almost entirely stored in astrocytes: polyamines that can be released through various mechanisms. Polyamine putrescine (PUT) is an important source of astrocyte GABA production. Significant GABA release suggests that the astrocyte Glu-GABA exchange mechanism plays a key role in limiting ictal discharge [46]. In addition, polyamine spermine (SPM) is also accumulated in astrocytes but not neurons [33]. It can also modulate neuronal NMDA, AMPA, and kainate receptors [33]. This evidence may show a new mechanism for regulating iLTP.

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