Dendritic Ion Channel Trafficking and Plasticity

Abstract

Dendrites, the elaborate processes emerging from neuronal cell bodies, receive most excitatory synaptic inputs. Voltage- and calcium-gated ion channels are abundant in dendrites and modify the shape, propagation and integration of synaptic signals. These ion channels also determine intrinsic dendritic excitability and are therfore important for the induction and manifestation of Hebbian and non-Hebbian plasticity. Revealingly, dendritic channels have distinct expression patterns and biophysical properties from those present in other neuronal compartments. Recent evidence suggests that dendritic ion channels are locally regulated, perhaps contributing to different forms of plasticity. In this review, we will discuss the implications of regulating dendritic ion channel function and trafficking in the context of plasticity and information processing.

1. Introduction

Dendrites are extensive and elaborate processes emerging from the cell body of neurons. They occupy a large surface area and receive the majority of synaptic inputs¹. Their predominant function is in processing and transmitting synaptic signals to the cell body and axon initial segment, where, if threshold is reached, action potentials are initiated. This is an active process, as it is now known that dendrites possess an abundance of ion channels that are involved in receiving, transforming and relaying information to other parts of the neuron¹. These dendritic ion channels often differ in their biophysical properties and densities from those present in other neuronal compartments. Moreover, ion channel expression and properties may also differ within the dendritic arbor of a particular neuron – e.g. hyperpolarization-activated cation non-selective (HCN) channels are expressed highly in the apical, but not the basal, dendritic tree of layer V cortical pyramidal neurons^2-4. This adds an additional layer of complexity to neuronal information processing.

Recent evidence suggests that selective targeting mechanisms determine the distribution and properties of dendritic ion channels⁵. Specific molecules are involved in the transport of voltage-gated ion channel subunits from the soma to dendrites. Additionally, mRNA can be trafficked into dendrites and locally translated, a process which may be activity-dependent⁶. Indeed, dendrites contain the necessary machinery that enables local protein synthesis⁷. Hence, expression of ion channels can be dynamically regulated in dendrites in response to changes in either pre- or post-synaptic activity and may present a sophisticated mechanism by which neurons gate information flow and thereby, neuronal output.

Changes in synaptic strength or connectivity are commonly thought to influence cellular information processing and thus, neural circuitry⁸. Modifications in synaptic drive can lead to various forms of plasticity, including long term potentiation (LTP) and long term depression (LTD) (see Glossary Box). To keep neuronal activity levels steady, the gain of individual synaptic strengths can be varied to oppose the change in synaptic drive, known as homeostatic plasticity. In addition, the properties and expression of voltage-gated ion channels can be persistently modulated, referred to as intrinsic plasticity (see Glossary Box).

Consequently, neuronal firing patterns may adjust, leading to changes in neural network activity and potentially physiological processes such as learning and memory. Intriguingly, this can occur at the level of individual branches of the dendritic tree⁹. Moreover, new evidence suggests that these changes can be due to altered trafficking of dendritic ion channels^10-19.

In this review, we discuss our current knowledge of dendritic ion channel trafficking and its relationship to cellular and synaptic plasticity and the implications for neuronal function. We argue that to gain insight into neuronal computation, it is essential to understand the regulation of dendritic ion channel expression and function. Since there have been many recent reviews on ligand--gated ion channel trafficking and plasticity (for example see20, 21), here we will focus on dendritic voltage-gated ion channel targeting mechanisms and plasticity.

2 Dendritic K⁺ channel targeting and plasticity

Potassium (K⁺) channels are essential for the regulation of neuronal excitability. In neurons, they are involved in a variety of functions including setting of the resting membrane potential, controlling the initiation and shape of single action potentials and determining the amplitude and kinetics of the afterhyperpolarization that follows an action potential²². These K⁺ channel functions are achieved through their molecular diversity and by dynamic regulation of their membrane distribution and biophysical properties. K⁺ channels consist of primary pore-forming (α) subunits and auxiliary (β) subunits. Currently, over 70 different genes encoding for the K⁺ channel α subunit are known. However, based on the structure of the α subunit, K⁺ channels can be broadly classified into three main families: the six transmembrane (6TM) subunit, the four transmembrane (4TM) subunit and the two transmembrane (2TM subunit families²³. The voltage-gated K⁺ (Kv) and calcium-activated K⁺ (KCa) channels fall into the 6TM family while the tandem two pore-domain (K2P) and inward rectifiers (Kir) form the 4TM and 2TM families respectively. Dendrites of central neurons contain members of all three families. Here we present recent findings from three of the four major classes of K⁺ channels, omitting background tandem two-pore K⁺ channels (K2P), which were the centre of recent reviews²⁴.

2.1 Kv channels

In many central neurons, the densities of most Kv channels appear to be uniform or lower in distal dendrites compared with those present at the soma¹. The exception appears to be the Kv4 subunit. Immunohistochemical analysis first showed that the Kv4 subunit was expressed predominantly in dendrites of several central neurons including hippocampal CA1 pyramidal, cerebellar granule and olfactory mitral cells^25-27. The Kv4 subunits form a fast activating and inactivating current in heterologous systems, reminiscent of the A-type K⁺ current (I_A) in neurons²⁸. Consistent with the immunohistochemical observations, electrophysiological data together with pharmacology and voltage-sensitive and calcium imaging have shown that the A-type K⁺ channel is present at a higher density in the apical^29-32 radial oblique^{9, 33-35} and basal^{4, 9, 36} dendrites than the soma of several types of central neurons. There, they play an important role in determining the amplitude and width of back-propagating action potentials^{29, 30, 32, 34, 36, 37}. They also limit the propagation of local dendritic spikes generated by spatially clustered and temporal synaptic input^{9, 35}. Further, these channels curtail dendritic Ca²⁺ signals generated by synaptic input or by back-propagating action potentials^{33, 34, 36, 38}. Thus, these channels affect forms of plasticity that depend on back-propagating action potentials or the propagation of local dendritic spikes (i.e. spike timing-dependent plasticity^{39, 40 9}) but not others (i.e. LTP triggered using a 100 Hz stimulation protocol³⁹).

Kv4.2 subunits contain a dileucine motif on the C-terminus that appears to dictate their dendritic localization (Figure 1)⁴¹. The kinesin isoform, Kif17 is also involved in dendritic transport of Kv4.2⁴². Kv4.2 cell surface expression is further regulated by a number of auxiliary subunits, Kv channel interacting proteins (KChIPs) and dipeptidyl peptidase-like type II proteins, DPP6 and DPP10 (Figure 1)²⁷. In addition, Kv4.2 subunits are modulated by a variety of kinases such as PKA, PKC and ERK/MAPK (Figure 1)⁴³. Hence, a diverse range of signalling molecules modify Kv4.2 subunit expression and biophysical characteristics.

Figure 1. NMDA receptor-dependent trafficking of K⁺ channels.

A) Model of NMDAR-dependent K⁺ channel trafficking that occurs during cellular and synaptic plasticity (1) During LTP, Kv4.2 and SK channels are internalized via PKA activation (2) Depotentiation is mediated by Girk2 synaptic insertion after protein phosphatase-1 activation(3) Intrinsic excitability is altered by the lateral translocation of Kv2.1 channels after protein phosphatase-2B activation. Relevant figures from the original reports are shown below in B1-3. B1) K⁺ channel internalization during LTP. B1i) Activity-dependent internalization of Kv4.2 requires NMDAR activation. Fluorescence changes are plotted from time-lapse images of spines from hippocampal neurons coexpressing EGFP-tagged Kv4.2 and a soluble red-fluorescent protein (tdTomato). AMPA stimulation progressively decreased Kv4.2 fluorescence intensity in spines, with no significant change in tdTomato fluorescence (inset). Kv4.2 fluorescence intensity was not significantly changed with APV coapplication to block NMDARs. (Adapted from Ref. [46]). B1ii) Activity-dependent internalization of SK channels in hippocampal slices after LTP. EPSPs were evoked from two independent pathways: a control pathway with no LTP induction (closed, black symbols) and a theta-burst pairing (TBP) stimulated pathway with robust LTP induction (open, blue symbols). Forty minutes after induction, stimulus strength was reduced to produce EPSPs of comparable slope in both pathways (blue shaded bar). Internalization of SK channels after LTP is observed by the lack of effect of the SK channel blocker apamin, on EPSP slope in the TBP pathway (blue) compared to the control (black) pathway (Adapted from Ref. [12]). B2) Activity-dependent insertion of GIRK2 in cultured hippocampal neurons. Left, immunostaining of hippocampal neurons with anti-GIRK2 C-terminal (red) and anti-synaptophysin antibodies (green) demonstrating synaptic localization of GIRK2. Arrows point to excitatory synapses on dendritic spines, whereas arrowheads point to inhibitory synapses on dendritic shafts. (Scale bar, 2 μm.). Right, activation of NMDARs t with NMDA and glycine elevated surface expression of GIRK1 and GIRK2 by ∼2-fold but not of the NMDAR subunit NR1. Similar results were found with synaptic NMDAR activation (Adapted from Ref. [15]). B3) Activity-dependent translocation of Kv2.1. Stimulation of cultured hippocampal neurons with glutamate dispersed Kv2.1 (adapted from Ref. [17]).

Since many forms of cellular and synaptic plasticity result in altered activity of kinases and phosphatases, it is perhaps not surprising that activity-dependent changes also affect dendritic Kv4.2 expression and properties. Indeed, in hippocampal CA1 neurons, increased PKA and MAPK activity following spike-timing dependent plasticity shifts the activation curve of I_A such that the amplitude of backpropagating action potentials are boosted^{44, 45}. Moreover, dendritic Kv4.2 subunits are internalized after chemical neuronal activation (e.g. AMPA, KCl, or glycine) or LTP induction (Figure 1Bli)⁴⁶. This activity- dependent internalization of Kv4.2 requires NMDA receptor activation, PKA activity and clatherin-mediated endocytosis^{10, 46, 47}. Since Kv4.2 expression reduces action potential back-propogation, the downregulation of dendritic Kv4.2 during synaptic stimulation is likely to increase back-propagation and the probability of spike-timing dependent plasticity. In addition, activity-dependent alterations in Kv4.2 channel expression influence NR2A/2B subunit expression and consequentially, metaplasticity¹¹. These exciting findings raise the possibility that the input specificity of synaptic plasticity may in part be mediated by alterations in local dendritic Kv channel expression.

Regulation of local protein synthesis and lateral translocation of Kv channels (Figure 1B3) are also mechanisms by which their differential expression occurs. Kv1.1 channels are locally translated in dendrites, and their translation is upregulated upon NMDA receptor inhibition, suggesting that activity-driven suppression of local translation can regulate K⁺ channel expression¹⁹. In pyramidal neurons, clustered somatodendritic Kv2.1 channels disperse laterally along the membrane after neuronal stimulation and dephosphorylation by PP2B (calcineurin)^{17, 48, 49}. This dephosphorylation and translocation is accompanied by a hyperpolarizing shift in the activation and inactivation of Kv2.1^{18, 49}. Interestingly, this effect is mediated by the activation of extrasynaptic NMDA receptors, and may be important for the regulation of intrinsic excitability of neurons during excitotoxic events^{18, 48, 49}. Together, these studies highlight the diverse mechanisms that regulate dendritic Kv subunit trafficking and expression following changes in synaptic drive and intrinsic excitability.

2.2 K_Ca Channels

K_Ca channels are distinguished from K_v channels by their Ca²⁺-dependent activation. Three types exist: small-conductance (K_Ca2.1-3, SK), intermediate-conductance (K_Ca3.1, IK) and large conductance (K_Ca1.1, BK)²³. K_Ca1 and K_Ca2 channels are present in principle dendrites of cerebellar purkinje cells⁵⁰ and olfactory bulb neurons^{51, 52} where they are involved in limiting burst firing and dendro-dendritic inhibition respectively. Recent findings suggest that K_Ca2 subunits may also be present in hippocampal distal dendrites where they are likely to have a role in limiting compartmentalized spikes triggered by strong synaptic input³⁸. Intriguingly, many recent studies have shown that K_Ca1 and K_Ca2 are located in close proximity to synaptic and extra-synaptic glutamate receptors in a variety of neuronal subtypes including olfactory bulb neurons⁵¹, hippocampal CA1 neurons^{53, 54}, lateral amygdala neurons⁵⁵ and amacrine cells⁵⁶. Their location in dendritic spines as well as their calcium dependence makes them ideal modulators of synaptic potential amplitude and kinetics as well as plasticity. Indeed, in the hippocampus and the amygdala, the hyperpolarization mediated by K_Ca2 channel activation by Ca²⁺ influx through NMDA receptors has been demonstrated to affect the threshold for synaptic plasticity induction^{53, 55} and the encoding of memories^{57, 58}.

As yet, very little is known about the mechanisms involved in targeting K_Ca channels to dendrites and spines. Recent evidence, though, suggests that basal levels of activated PKA may also be involved in synaptic recycling of K_Ca2.2 channels⁵⁹. Further, like Kv4.2 subunits (see above), induction of synaptic plasticity in hippocampal neurons results in K_Ca2.2 internalisation (Figure 1B1ii), potentially enhancing metaplasticity¹². This effect is also NMDAR-dependent and mediated by phosphorylation of K_Ca2.2 by PKA¹². Hence, similar mechanisms appear to be engaged in regulation of dendritic Kv4 and K_Ca channel expression.

2.3 Kir channels

K_ir channels are formed by four homo- or heteromeric alpha subunits, each with 2 transmembrane domains²³. There are 7 subfamilies, Kir1-7, which differ in the degrees of rectification and their coupling to intracellular molecules⁶⁰. An internal block conveys the unidirectional inward rectification of Kir channels by polyamines and Mg²⁺ ions⁶¹, with the strength of rectification proportional to the channel's affinity for blocking cations. At membrane potentials more negative than rest, K_ir channels pass an inward/depolarizing K⁺ current, returning the membrane to resting potential. However, at potentials more positive than rest, intracellular cation block prevents outward K⁺ current from hyperpolarizing the cell membrane. These fundamental rectification properties of K_ir channels are essential in maintaining neuronal membrane potential.

There is considerable evidence that Kir3.x channels are situated in the apical dendrites and spines of neocortical and hippocampal CA1 neurons^62-65. K_ir3.x channels are also unique in that they are activated by G proteins and thus, G-protein coupled receptors such as GABA_B receptors⁶⁶. The synaptic location of Kir channels indicates that their current may be modulated by changes in synaptic strength. Indeed, slow IPSCs mediated by GABA_B receptors and GIRK channels are potentiated following low frequency (3 Hz) stimulation⁶⁷. This effect is NMDA receptor and CaMKII dependent.

Recent evidence shows that GIRK channel expression is also regulated by activity. Enhanced neuronal activity with KCl, glutamate, NMDA or glycine, which reduce Kv4.2 and K_Ca surface expression, elevate K_ir3.1 and K_ir3.2 channels in hippocampal dendrites (Figure 1B2)¹⁵. This occurs through NMDA receptor-dependent activation of a phosphatase, PP1, which dephosphorylates K_ir3.1-2 channels, causing their insertion into the membrane from recycling endosomes. NMDA receptor-dependent insertion of K_ir3.1-2 channels mediates the depotentiation (see Glossary Box) of EPSPs after LTP induction⁶⁸ and may be important in maintaining bidirectional modification of synapses.

3. Dendritic HCN channel function and trafficking: role in plasticity?

Hyperpolarization-activated Cation Non-Selective (HCN) subunits are comprised of four, six-transmembrane spanning α subunits (similar to Kv channels) (Figure 2)⁶⁹. The channels formed by the subunits are also voltage dependent and usually activate at potentials hyperpolarized to -50 mV. Unlike Kv channels, though, the channels are permeable to both Na⁺ and K⁺. They therefore form a depolarizing current, which is involved in maintaining the neuronal resting membrane potential (RMP). Further, they also affect the membrane time constant and membrane resistance⁶⁹. Hence, alterations in expression and biophysical characteristics of HCN channels can have profound effects on neuronal excitability.

Figure 2. Structure and function of dendritic HCN channels.

A) Illustration of TRIP8b and PEX5Rp interaction with the C-terminus of HCN subunits. The Cyclic Nucleotide Binding Domain (CNBD) which binds to cAMP is also located on the C-terminus. B) Confocal images showing TRIP8b and HCN1 expression in cortical layer V cell dendrites. The right panel shows the merged image of rhodamine-red labelled anti-TRIP8b and FITC labelled anti-HCN1. Co-localization is depicted as yellow on this image. The double staining was obtained in the same brain section (adapted from Ref. [92]).

Four HCN subunits (HCN1-4) have so far been cloned⁷⁰. Interestingly, the apical, but not basal, dendrites of adult cortical and hippocampal pyramidal cells are enriched with HCN1 and HCN2 subunits^{2, 3, 69, 71-73}. Their effects on dendritic excitability, though, are complex. Although block or knockdown of HCN channels results in RMP hyperpolarization, significantly greater numbers of dendritic action potentials can be induced by current pulses due to a disproportionate enhancement in membrane resistance^{74, 75}. Additionally, by affecting the membrane resistance, a reduction in I_h increases synaptic potential decay and thereby summation^74-79. Consequentially, loss of I_h in distal hippocampal dendrites leads to enhanced LTP⁸⁰. Further, due to greater EPSP summation, stimulation of distal synapses of cortical pyramidal cell dendrites lacking HCN1 channels elicits somatic action potentials, despite the RMP being more negative than in wildtype neurons⁷⁴. Thus, as a result of greater pyramidal cell output, neural network excitability is elevated following either pharmacological block or deletion of HCN subunits^{14, 74}. Since alterations in dendritic I_h biophysical characteristics and HCN subunit expression patterns can affect intrinsic cell excitability as well as network stability, it is not surprising that changes in I_h have been associated with physiological processes such as learning and memory^{14, 80-82} as well as pathophysiological conditions such as epilepsy^{75, 83-85}.

HCN subunits have a cyclic nucleotide binding domain on the C-terminal (Figure 2)⁶⁹. Indeed, alterations in levels of cAMP shifts the activation curve of I_h ^{86, 87}. cAMP activity is also altered following synaptic and intrinsic plasticity and is one mechanism by which dendritic HCN biophysical properties can change. Indeed, a recent elegant study by Wang et al. (2007)¹⁴ demonstrated that stimulation of α2 adrenoreceptors in prefrontal cortical neuron spines reduced HCN function andreinforced working memory. This study highlights how regulation of HCN channel activity can profoundly impact network activity and behavior, an effect dependent on cAMP.

Changes in synaptic strength have also been shown to modify I_h by altering intracellular Ca²⁺ concentration and associated downstream signalling molecules, including calcium/calmodulin dependent protein kinase II (CaMKII) and protein kinase C (PKC), activity^{81, 88, 89}. Interestingly, pharmacological inhibition of synaptic activity or CaMKII prevents enrichment of HCN1 channels in distal hippocampal CA1 apical dendrites, suggesting that activity-dependent CaMKII activation is involved in dendritic trafficking of HCN channels^{90, 91}.

Several recent studies have identified multiple isoforms of TPR-containing Rab8b interacting protein (TRIP8b) and pex5p-related protein (PEX5Rp) that associate with HCN subunits (Figure 2). Immunohistochemical studies have shown these to be co-localized with HCN1 in hippocampal and cortical apical dendrites (Figure 2) ^92-95. These proteins are involved in regulating the expression of HCN channels too^92-95. Intriguingly, excessive neuronal activity as occurs during seizures reduces TRIP8b expression in addition to HCN subunit levels in hippocampal neurons¹³, indicating that selective isoforms of TRIP8b may be subject to activity-dependent regulation. This could therefor be a potential mechanism underlying changes in HCN expression following modified neuronal activity^{81, 88, 90, 96}.

Although multiple pathways have been implicated in HCN dendritic trafficking, are they interconnected? CaMKII and PKC phosphorylation consensus sites are present on HCN subunits as well as on TRIP8b isoforms^{95, 97}. Therefore, it is tempting to speculate that variations in activity of signalling molecules such as CaMKII and PKC locally in dendrites following plasticity, may represent a means by which TRIP8b and HCN channel subunit levels can be dynamically regulated. Since HCN subunits are important for maintaining dendritic excitability and synaptic signal shapes and integration (Figure 2), changes in TRIP8b isoform expression are likely to result in altered neuronal information processing. Further studies, though, are required to determine if the various forms of plasticity (see Glossary Box) lead to differing levels of TRIP8b isoforms and the underlying cellular mechanisms responsible.

3. Voltage-gated Ca²⁺ channel plasticity in dendrites and spines

To date, ten voltage-gated Ca²⁺ channel (VGCC) primary subunits have been cloned. These can be further subdivided into 3 families: 1) dihydropyridine-sensitive high voltage-activated, Ca_V1.x (L-type); 2) dihydropyradine- insensitive high voltage-activated, Ca_V2.x (N-, P-, Q- and R- types); and 3) low voltage-activated, Ca_V3.x (T-type)²³. Immunohistochemical as well as electrophysiological studies have revealed the presence of all subtypes of VGCC in dendrite shafts⁹⁸, although the distribution of the various subtypes may differ within these structures across neuronal subtypes. For example in hippocampal CA1 neurons, Ca_V1.x Ca²⁺ channels are predominantly present at the base of the apical dendrites⁹⁹ while Ca_V2.3 and Ca_V3.x Ca²⁺ channels located at a higher density in distal dendrites compared to the soma^{100, 101}. In thalamocortical neurons, on the other hand, Ca_V3.x channels are found at a high density selectively in proximal dendrites¹⁰² where they may play a role in shaping rhythmic bursting¹⁰³. Further, multiple subtypes of VGCC have been found in dendritic spines in numerous cell types¹⁰⁴.

As yet, the factors that permit VGCC to be targeted specifically to dendrites and spines are unknown. However, VGCC activity in dendritic shafts as well as spines is likely to be a mechanism for the induction and maintenance of multiple forms of plasticity, including spike timing dependent plasticity. VGCC opening is enhanced by action potential backpropagation as well as synaptic potential generation^{98, 104} and Ca²⁺ entry through VGCC is important for intracellular signalling¹⁰⁵. Indeed, Ca²⁺ entry through dendritic VGCC is necessary for LTD in entorhinal cortical cells¹⁰⁶ and hippocampal CA1 neurons¹⁰⁷, as well as for LTP at hippocampal CA1- perforant path synapses¹⁰⁸ and hippocampal CA1-schaffer collatoral synapses¹⁰⁹. Moreover, Ca²⁺ influx via Ca_V1.x (L-type) Ca²⁺ channels in dendritic spines contributes to induction of synapse specific NMDA receptor- dependent LTP in hippocampal neurons¹¹⁰. Like Kv4.2 and K_Ca channels, these may also form signalling complexes with NMDA receptors in hippocampal spines¹¹⁰. The raised Ca²⁺ concentration within individual spines can then activate a cascade of intracellular substances including CaMKII and cAMP which can lead to modification of the activity of additional spine VGCC such as Ca_V2.3 channels¹¹¹. Further, L-type Ca²⁺ channel activity in spines is enhanced in a PKA-dependent manner by noradrenaline acting on beta-adrenoreceptors¹¹², perhaps increasing the likelihood of plasticity occurring at selective synapses. Hence, the resting state of VGCC activity in spines and dendrites may be important for neuronal information processing and plasticity.

Concluding remarks

In this article, we have discussed the involvement of dendritic ion channels in determining the threshold and manifestation of various forms of plasticity as well as how plasticity in turn affects the expression and function of these channels. In particular, we have examined how dendritic K⁺, HCN and Ca²⁺ channels contribute to an intricate signalling complex within dendriticspines and shafts, which under physiological conditions regulates post-synaptic plasticity and intrinsic excitability. While we have focussed on K⁺, HCN and Ca²⁺ channels, dendrites contain all known superfamilies of voltage-gated ion channels^{1, 98}. Much less is known about how these other channel subtypes are selectively targeted to dendrites and whether plasticity affects the dendritic trafficking of these channels. Nonetheless, it is clear that local expression and regulation of dendritic voltage-gated ion channel properties can provide dendrites with a dynamic tuning mechanism to adjust to changes in synaptic strength and thereby modify information processing.

Glossary Box: Neuronal Plasticity.

Since Bliss and Lomo first described the phenomenon of long-term potentiation ^{1, 2}, great strides have been made in understanding synaptic plasticity. The elegance of this discovery was evident when considered in the context of Hebb's postulate for cellular learning³. Here, Hebb described fundamental properties involved in the strengthening of synapses, such as cooperation and coincidence (multiple inputs firing coincidentally cause strengthening) and input specificity (only synapses at active inputs are strengthened). Synaptic plasticity following these principles is often referred to as Hebbian plasticity. Decades later, it is clear that multiple forms of plasticity- both synaptic and cellular (non synapse-specific) coexist in the brain, shaping information processing and storage, and ultimately complex behavior. Here, we provide a glossary of terms for some of these diverse forms of cellular plasticity, with relevant reviews cited for each.

Synaptic Plasticity⁴

refers to short-term or long-term changes in the ability of a presynaptic input to alter the postsynaptic response (synaptic efficacy).

Long-term potentiation (LTP) and Long-term depression (LTD)

are long-term increases or decreases in synaptic efficacy, respectively. Classically, LTP and LTD were examined at Schaeffer collateral-CA1 synapses and characterized as NMDAR-dependent⁵. This form of synaptic plasticity requires postsynaptic Ca²⁺ entry through voltage-sensitive NMDA receptors, positioning dendritic ion channels as regulators of NMDAR-dependent synaptic plasticity. However, we now know there are other forms of LTP and LTD with distinct molecular mechanisms. For example, mGluR-dependent LTD is a well described NMDAR-independent LTD ⁶ found throughout the brain that requires mGluR1/5 activation and protein synthesis for induction.

Spike-timing dependent plasticity (STDP)^{7, 8}

refers to LTP or LTD elicited through pairing single pre- and post-synaptic action potentials, such as presynaptic firing coincident with a back-propagating action potential (bp-AP). The precise timing of these two events confers both the magnitude and direction of plasticity. Dendritic ion channels are important regulators of STDP, since they maintain membrane properties and control the spread of bpAPs in dendrites^{9, 10}.

Depotentiation

is a sustained reduction in synaptic efficacy occurring after LTP. This reversal of LTP is thought to function as a synaptic “reset”, preventing LTP saturation and positioning the synapse for further bidirectional modification.

Metaplasticity¹¹

refers to biological changes that the inducibility of plasticity (or as the prefix suggests, metaplasticity is the “plasticity of plasticity”). With respect to synaptic plasticity, metaplasticity was first described in the BCM model¹² as alterations in the threshold for the induction of synaptic plasticity (or modification threshold).

Intrinsic Plasticity^13-15

refers to alterations in local or cell-wide excitability, such that the input / output function of the postsynaptic neuron is changed. Intrinsic plasticity is governed by changes in the expression and activation of dendritic ion channels, which largely control membrane excitability. Interestingly, intrinsic plasticity can occur in parallel with synaptic plasticity and may also serve as a mechanism for metaplasticity (eg: with increased intrinsic excitability reducing the modification threshold, and reduced intrinsic excitability stabilizing the neuron by increasing the modification threshold).

Homeostatic Plasticity^{13, 16-18}

refers to global, stabilizing changes in the postsynaptic neuron, such as changes in dendritic ion channel expression. Homeostatic plasticity can provide negative feedback control over neuronal strength, and is important for maintaining neuronal activity within a dynamic functional range. This can occur through synaptic scaling, where global changes occur while maintaining relative synaptic weights, through intrinsic plasticity, or through synaptic changes in the modification threshold.