Decreases in CaMKII activity trigger persistent potentiation of intrinsic excitability in spontaneously firing vestibular nucleus neurons

Calcium/calmodulin-dependent protein kinase II (CaMKII) has been described as a biochemical switch that is turned on by increases in intracellular calcium to mediate synaptic plasticity. Here, we show that reductions in CaMKII activity trigger persistent increases in intrinsic excitability. In spontaneously firing vestibular nucleus neurons, CaMKII activity is near maximal, and blockade of CaMKII activity increases excitability by reducing BK-type calcium-activated potassium currents. Firing rate potentiation, a form of plasticity in which synaptic inhibition induces long-lasting increases in excitability, is occluded by prior blockade of CaMKII and blocked by addition of constitutively active CaMKII. Reductions in CaMKII activity are necessary and sufficient to induce firing rate potentiation and may contribute to motor learning in the vestibulo-ocular reflex.     

A Dynamical Role for Acetylcholine in Synaptic Renormalization

Although sleep is a fundamental behavior observed in virtually all animal species, its functions remain unclear. One leading proposal, known as the synaptic renormalization hypothesis, suggests that sleep is necessary to counteract a global strengthening of synapses that occurs during wakefulness. Evidence for sleep-dependent synaptic downscaling (or synaptic renormalization) has been observed experimentally, but the physiological mechanisms which generate this phenomenon are unknown. In this study, we propose that changes in neuronal membrane excitability induced by acetylcholine may provide a dynamical mechanism for both wake-dependent synaptic upscaling and sleep-dependent downscaling. We show in silico that cholinergically-induced changes in network firing patterns alter overall network synaptic potentiation when synaptic strengths evolve through spike-timing dependent plasticity mechanisms. Specifically, network synaptic potentiation increases dramatically with high cholinergic concentration and decreases dramatically with low levels of acetylcholine. We demonstrate that this phenomenon is robust across variation of many different network parameters.     

Less means more: inhibition of spontaneous firing triggers persistent increases in excitability

Modulation of intrinsic excitability is an alternative to classical synaptic plasticity for implementing activity-dependent changes in neuronal networks. In this issue of Neuron, Nelson et al. reveal a new form of plasticity of intrinsic excitability that can be triggered rapidly when synaptic inhibition reduces spontaneous firing, resulting in persistent enhancement of firing rate and neuronal gain.     

DPP6 establishes the A-type K(+) current gradient critical for the regulation of dendritic excitability in CA1 hippocampal neurons

Subthreshold-activating A-type K(+) currents are essential for the proper functioning of the brain, where they act to delay excitation and regulate firing frequency. In CA1 hippocampal pyramidal neuron dendrites, the density of A-type K(+) current increases with distance from the soma, playing an important role in synaptic integration and plasticity. The mechanism underlying this gradient has, however, remained elusive. Here, dendritic recordings from mice lacking the Kv4 transmembrane auxiliary subunit DPP6 revealed that this protein is critical for generating the A-current gradient. Loss of DPP6 led to a decrease in A-type current, specifically in distal dendrites. Decreased current density was accompanied by a depolarizing shift in the voltage dependence of channel activation. Together these changes resulted in hyperexcitable dendrites with enhanced dendritic AP back-propagation, calcium electrogenesis, and induction of synaptic long-term potentiation. Despite enhanced dendritic excitability, firing behavior evoked by somatic current injection was mainly unaffected in DPP6-KO recordings, indicating compartmentalized regulation of neuronal excitability.     

A Calcium-Dependent Plasticity Rule for HCN Channels Maintains Activity Homeostasis and Stable Synaptic Learning

Theoretical and computational frameworks for synaptic plasticity and learning have a long and cherished history, with few parallels within the well-established literature for plasticity of voltage-gated ion channels. In this study, we derive rules for plasticity in the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, and assess the synergy between synaptic and HCN channel plasticity in establishing stability during synaptic learning. To do this, we employ a conductance-based model for the hippocampal pyramidal neuron, and incorporate synaptic plasticity through the well-established Bienenstock-Cooper-Munro (BCM)-like rule for synaptic plasticity, wherein the direction and strength of the plasticity is dependent on the concentration of calcium influx. Under this framework, we derive a rule for HCN channel plasticity to establish homeostasis in synaptically-driven firing rate, and incorporate such plasticity into our model. In demonstrating that this rule for HCN channel plasticity helps maintain firing rate homeostasis after bidirectional synaptic plasticity, we observe a linear relationship between synaptic plasticity and HCN channel plasticity for maintaining firing rate homeostasis. Motivated by this linear relationship, we derive a calcium-dependent rule for HCN-channel plasticity, and demonstrate that firing rate homeostasis is maintained in the face of synaptic plasticity when moderate and high levels of cytosolic calcium influx induced depression and potentiation of the HCN-channel conductance, respectively. Additionally, we show that such synergy between synaptic and HCN-channel plasticity enhances the stability of synaptic learning through metaplasticity in the BCM-like synaptic plasticity profile. Finally, we demonstrate that the synergistic interaction between synaptic and HCN-channel plasticity preserves robustness of information transfer across the neuron under a rate-coding schema. Our results establish specific physiological roles for experimentally observed plasticity in HCN channels accompanying synaptic plasticity in hippocampal neurons, and uncover potential links between HCN-channel plasticity and calcium influx, dynamic gain control and stable synaptic learning.     

Bidirectional plasticity gated by hyperpolarization controls the gain of postsynaptic firing responses at central vestibular nerve synapses

Linking synaptic plasticity with behavioral learning requires understanding how synaptic efficacy influences postsynaptic firing in neurons whose role in behavior is understood. Here, we examine plasticity at a candidate site of motor learning: vestibular nerve synapses onto neurons that mediate reflexive movements. Pairing nerve activity with changes in postsynaptic voltage induced bidirectional synaptic plasticity in vestibular nucleus projection neurons: long-term potentiation relied on calcium-permeable AMPA receptors and postsynaptic hyperpolarization, whereas long-term depression relied on NMDA receptors and postsynaptic depolarization. Remarkably, both forms of plasticity uniformly scaled synaptic currents evoked by pulse trains, and these changes in synaptic efficacy were translated into linear increases or decreases in postsynaptic firing responses. Synapses onto local inhibitory neurons were also plastic but expressed only long-term depression. Bidirectional, linear gain control of vestibular nerve synapses onto projection neurons provides a plausible mechanism for motor learning underlying adaptation of vestibular reflexes.     

Histamine Receptor Expression, Hippocampal Plasticity and Ammonia in Histidine Decarboxylase Knockout Mice

Genetic ablation of the histamine producing enzyme histidine decarboxylase (HDC) leads to alteration in exploratory behaviour and hippocampus-dependent learning. We investigated how brain histamine deficiency in HDC knockout mice (HDC KO) affects hippocampal excitability, synaptic plasticity, and the expression of histamine receptors. No significant alterations in: basal synaptic transmission, long-term potentiation (LTP) in the Schaffer collateral synapses, histamine-induced transient changes in the CA1 pyramidal cell excitability, and the expression of H1 and H2 receptor mRNAs were found in hippocampal slices from HDC KO mice. However, when compared to WT mice, HDC KO mice demonstrated: 1. a stronger enhancement of LTP by histamine, 2. a stronger impairment of LTP by ammonia, 3. no long-lasting potentiation of population spikes by histamine, 4. a decreased expression of H3 receptor mRNA, and 5. less potentiation of population spikes by H3 receptor agonism. Parallel measurements in the hypothalamic tuberomamillary nucleus, the origin of neuronal histamine, demonstrated an increased expression of H3 receptors in HDC KO mice without any changes in the spontaneous firing of “histaminergic” neurons without histamine and their responses to the H3 receptor agonist (R)-α-methylhistamine. We conclude that the absence of neuronal histamine results in subtle changes in hippocampal synaptic transmission and plasticity associated with alteration in the expression of H3 receptors.     

Maintenance of postsynaptic neuronal excitability by a positive feedback loop of postsynaptic BDNF expression

Experiments have demonstrated that in mice, the PVT strongly projects to the CeL and participates in the formation of fear memories by synaptic potentiation in the amygdala. Herein, we propose a mathematical model based on a positive feedback loop of BDNF expression and signaling to investigate PVT manipulation of synaptic potentiation. The model is validated by comparisons with experimental observations. We find that a high postsynaptic firing frequency after stimulation is induced by presynaptic \({\rm {Ca}^{2+}}\) when the rates of BDNF secretion from PVT and LA neurons to the CeL are above a threshold value. Moreover, the positive feedback of postsynaptic BDNF production is important for the maintenance of the high excitability of the \({\rm SOM^+}\) CeL neuron after stimulation. The model brings insight into the underlying mechanisms of PVT modulation of synaptic potentiation at LA-CeL synapses and provides a framework of understanding other similar processes associated with synaptic plasticity.     

Place representation within hippocampal networks is modified by long-term potentiation

In the brain, information is encoded by the firing patterns of neuronal ensembles and the strength of synaptic connections between individual neurons. We report here that representation of the environment by "place" cells is altered by changing synaptic weights within hippocampal networks. Long-term potentiation (LTP) of intrinsic hippocampal pathways abolished existing place fields, created new place fields, and rearranged the temporal relationship within the affected population. The effect of LTP on neuron discharge was rate and context dependent. The LTP-induced "remapping" occurred without affecting the global firing rate of the network. The findings support the view that learned place representation can be accomplished by LTP-like synaptic plasticity within intrahippocampal networks.     

The Role of Proteases in Hippocampal Synaptic Plasticity: Putting Together Small Pieces of a Complex Puzzle

Long-term synaptic plasticity in the hippocampus is thought to underlie the formation of certain forms of memory, including spatial memory. The early phase of long-term synaptic potentiation and synaptic depression depends on post-translational modifications of synaptic proteins, while protein synthesis is also required for the late-phase of both forms of synaptic plasticity (L-LTP and L-LTD). Numerous pieces of evidence show a role for different types of proteases in synaptic plasticity, further increasing the diversity of mechanisms involved in the regulation of the intracellular and extracellular protein content. The cleavage of extracellular proteins is coupled to changes in postsynaptic intracellular mechanisms, and additional alterations in this compartment result from the protease-mediated targeting of intracellular proteins. Both mechanisms contribute to initiate signaling cascades that drive downstream pathways coupled to synaptic plasticity. In this review we summarize the evidence pointing to a role for extracellular and intracellular proteases, with distinct specificities, in synaptic plasticity. Where in the cells the proteases are located, and how they are regulated is also discussed. The combined actions of proteases and translation mechanisms contribute to a tight control of the synaptic proteome relevant for long-term synaptic potentiation and synaptic depression in the hippocampus. Additional studies are required to elucidate the mechanisms whereby these changes in the synaptic proteome are related with plasticity phenomena.     

Arc/Arg3.1 mediates homeostatic synaptic scaling of AMPA receptors

Homeostatic plasticity may compensate for Hebbian forms of synaptic plasticity, such as long-term potentiation (LTP) and depression (LTD), by scaling neuronal output without changing the relative strength of individual synapses. This delicate balance between neuronal output and distributed synaptic weight may be necessary for maintaining efficient encoding of information across neuronal networks. Here, we demonstrate that Arc/Arg3.1, an immediate-early gene (IEG) that is rapidly induced by neuronal activity associated with information encoding in the brain, mediates homeostatic synaptic scaling of AMPA type glutamate receptors (AMPARs) via its ability to activate a novel and selective AMPAR endocytic pathway. High levels of Arc/Arg3.1 block the homeostatic increases in AMPAR function induced by chronic neuronal inactivity. Conversely, loss of Arc/Arg3.1 results in increased AMPAR function and abolishes homeostatic scaling of AMPARs. These observations, together with evidence that Arc/Arg3.1 is required for memory consolidation, reveal the importance of Arc/Arg3.1's dynamic expression as it exerts continuous and precise control over synaptic strength and cellular excitability.     

Increased neuronal excitability, synaptic plasticity, and learning in aged Kvbeta1.1 knockout mice

BACKGROUND: Advancing age is typically accompanied by deficits in learning and memory. These deficits occur independently of overt pathology and are often considered to be a part of "normal aging." At the neuronal level, normal aging is known to be associated with numerous cellular and molecular changes, which include a pronounced decrease in neuronal excitability and an altered induction in the threshold for synaptic plasticity. Because both of these mechanisms (neuronal excitability and synaptic plasticity) have been implicated as putative cellular substrates for learning and memory, it is reasonable to propose that age-related changes in these mechanisms may contribute to the general cognitive decline that occurs during aging. RESULTS: To further investigate the relationship between aging, learning and memory, neuronal excitability, and synaptic plasticity, we have carried out experiments with aged mice that lack the auxiliary potassium channel subunit Kvbeta1.1. In aged mice, the deletion of the auxiliary potassium channel subunit Kvbeta1.1 resulted in increased neuronal excitability, as measured by a decrease in the post-burst afterhyperpolarization. In addition, long-term potentiation (LTP) was more readily induced in aged Kvbeta1.1 knockout mice. Finally, the aged Kvbeta1.1 mutants outperformed age-matched controls in the hidden-platform version of the Morris water maze. Interestingly, the enhancements in excitability and learning were both sensitive to genetic background: The enhanced learning was only observed in a genetic background in which the mutants exhibited increased neuronal excitability. CONCLUSIONS: Neuronal excitability is an important determinant of both synaptic plasticity and learning in aged subjects.     

A Review of Aspects of Synaptic Plasticity in Hippocampus via mT Extremely Low-Frequency Magnetic Fields

The subthreshold magnetic modulation technique stimulates cells with mT extremely low-frequency magnetic fields (ELF-MFs), which are insufficient to induce neuronal action potentials. Although they cannot directly induce resting neurons to discharge, mT magnetic stimulation can regulate the excitability of the nervous system, which regulates learning and memory by some unknown mechanisms. Herein, we describe the regulation of mT ELF-MFs with different parameters on synaptic plasticity in hippocampal neurons. Additionally, we summarize the latest research on the possible mechanism of the effect of ELF-MFs on synaptic plasticity. Some studies have shown that ELF-MFs are able to inhibit long-term potentiation (LTP) by increasing concentration of intracellular Ca²⁺ concentration ([Ca²⁺]_i), as well as concentration of reactive oxygen species. The research in this paper has significance for the comprehensive understanding of relevant neurological mechanisms of learning and memory by mT ELF-MFs stimulation. However, more high-quality research is necessary to determine the regulatory mechanism of mT ELF-MFs on synaptic plasticity in order to optimize this technique as a treatment for neurological diseases. © 2023 Bioelectromagnetics Society.     

Differences in biophysical properties of nucleus accumbens medium spiny neurons emerging from inactivation of inward rectifying potassium currents

Inward rectifying potassium (K_IR) currents in medium spiny (MS) neurons of nucleus accumbens inactivate significantly in ~40% of the neurons but not in the rest, which may lead to differences in input processing by these two groups. Using a 189-compartment computational model of the MS neuron, we investigate the influence of this property using injected current as well as spatiotemporally distributed synaptic inputs. Our study demonstrates that K_IR current inactivation facilitates depolarization, firing frequency and firing onset in these neurons. These effects may be attributed to the higher input resistance of the cell as well as a more depolarized resting/down-state potential induced by the inactivation of this current. In view of the reports that dendritic intracellular calcium levels depend closely on burst strength and spike onset time, our findings suggest that inactivation of K_IR currents may offer a means of modulating both excitability and synaptic plasticity in MS neurons.     

Neurophysiological changes associated with selective neuronal damage in hippocampus following transient forebrain ischemia.

Neurophysiological changes of hippocampal neurons were compared before and after transient forebrain ischemia using intracellular recording and staining techniques in vivo. Ischemic depolarization (ID) was used as an indication of severe ischemia. Under halothane anesthesia, approximately 13 min of ID consistently produced severe neuronal damage in the CA1 region of rat hippocampus, while CA3 pyramidal neurons and dentate granule cells remained intact. After such severe ischemia, approximately 60% of the CA1 neurons exhibited a synaptic potentiation. The excitability of these neurons progressively decreased following reperfusion. Approximately 30% of the CA1 neurons showed a synaptic depression following ischemia. The excitability of these neurons transiently decreased following reperfusion. After ischemia of the same severity, both synaptic transmission and excitability of CA3 and granule cells transiently depressed. These data suggest that ischemia-induced synaptic potentiation may be associated with the pathogenesis of neuronal damage following ischemia, and that the synaptic depression may have protective effects on hippocampal neurons after ischemic insult.     

Heterosynaptic LTD of hippocampal GABAergic synapses: a novel role of endocannabinoids in regulating excitability

Neuronal excitability and long-term synaptic plasticity at excitatory synapses are critically dependent on the level of inhibition, and accordingly, changes of inhibitory synaptic efficacy should have great impact on neuronal function and neural network processing. We describe here a form of activity-dependent long-term depression at hippocampal inhibitory synapses that is triggered postsynaptically via glutamate receptor activation but is expressed presynaptically. That is, glutamate released by repetitive activation of Schaffer collaterals activates group I metabotropic glutamate receptors at CA1 pyramidal cells, triggering a persistent reduction of GABA release that is mediated by endocannabinoids. This heterosynaptic form of plasticity is involved in changes of pyramidal cell excitability associated with long-term potentiation at excitatory synapses and could account for the effects of cannabinoids on learning and memory.     

BDNF acutely modulates synaptic transmission and calcium signalling in developing cortical neurons.

Brain-derived neurotrophic factor (BDNF), like other neurotrophins, has long-term effects on neuronal survival and differentiation; furthermore, BDNF has been reported to exert an acute potentiation of synaptic activity and are critically involved in long-term potentiation(LTP). We found that BDNF rapidly induced potentiation of synaptic activity and an increase in the intracellular Ca2+ concentration in cultured cortical neurons. Within minutes of BDNF application to cultured cortical neurons, spontaneous firing rate was dramatically increased as was the frequency and amplitude of excitatory spontaneous postsynaptic currents (EPSCs). Fura-2 recordings showed that BDNF acutely elicited an increase in intracellular calcium concentration ([Ca2+]i). This effect was partially dependent on extracellular Ca2+. In calcium-free perfusion medium a substantial calcium signal remained which disappeared after loading of cortical neurons with 5 microM U-73122. BDNF-induce Ca2+ transients were completely blocked by K252a and partially blocked by Cd2+. The results demonstrate that BDNF can enhance synaptic transmission and induce directly a rise in [Ca2+]i that require two routes: the release of Ca2+ from intracellular calcium stores and influx of extracellular Ca2+ mainly through voltage-dependent Ca2+ channels in cultured cortical neurons.     

The spike-timing dependence of plasticity

In spike-timing-dependent plasticity (STDP), the order and precise temporal interval between presynaptic and postsynaptic spikes determine the sign and magnitude of long-term potentiation (LTP) or depression (LTD). STDP is widely utilized in models of circuit-level plasticity, development, and learning. However, spike timing is just one of several factors (including firing rate, synaptic cooperativity, and depolarization) that govern plasticity induction, and its relative importance varies across synapses and activity regimes. This review summarizes this broader view of plasticity, including the forms and cellular mechanisms for the spike-timing dependence of plasticity, and, the evidence that spike timing is an important determinant of plasticity in?vivo.     

Cognitive Aging: Recapturing the Excitation of Youth?

The electrical excitability of cortical neurons changes significantly during normal ageing. A recent study found that targeted deletion of a gene encoding a potassium channel-modifier subunit can restore to aged mice, not only normal neuronal firing, but also normal learning and synaptic plasticity.