Weak Synapses Research Articles

Dendritic Learning as a Paradigm Shift in Brain Learning.

Experimental and theoretical results reveal a new underlying mechanism for fast brain learning process, dendritic learning, as opposed to the misdirected research in neuroscience over decades, which is based solely on slow synaptic plasticity. The presented paradigm indicates that learning occurs in closer proximity to the neuron, the computational unit, dendritic strengths are self-oscillating, and weak synapses, which comprise the majority of our brain and previously were assumed to be insignificant, play a key role in plasticity. The new learning sites of the brain call for a reevaluation of current treatments for disordered brain functionality and for a better understanding of proper chemical drugs and biological mechanisms to maintain, control and enhance learning.

Augmentation of M‐Current and Increased Synaptic Efficacy at Intrinsic Cardiac Neurons Contributes to an Enhanced Cardiac Responsiveness to Vagal Nerve Stimulation in the Infarcted Porcine Heart

Imbalances to autonomic regulation of cardiac function contribute to risk for arrhythmia after myocardial infarction (MI). We tested the hearts responsiveness to vagal nerve stimulation (VNS), 8 wks after MI, to determine if parasympathetic control of the heart is altered in MI pigs. A significantly greater bradycardic response was elicited in MI animals during 20Hz stimulation. Intracellular voltage recordings from whole‐mount preparations of intrinsic cardiac neurons (ICNs) were subsequently used to assess whether alterations in neuronal membrane properties or synaptic transmission underlie the observed increase in responsiveness to VNS in MI animals. General membrane properties (resting membrane potential, input resistance, action potential amplitude/duration, afterhyperpolarization amplitude/duration) of ICNs from control and MI pigs were not different, but ICN excitability was significantly depressed in MI pigs. Testing synaptic efficacy revealed a greater proportion of strong (high AP probability) vs weak synapses (low AP probability) in MI animals. Tetanic stimulation (20Hz) of interganglionic nerve bundles elicited slow excitatory postsynaptic potentials (sEPSPs) in a significantly greater subset of MI ICNs (10/22) vs controls (4/26). The sEPSP persisted in hexamethonium (500uM) but was blocked by atropine (1uM), indicating mediation by cholinergic inhibition of M‐current. Application of 1mM Ba2+ increased excitability of ICNs from both control and MI animals further supporting a role for M‐current in the regulation of porcine ICN excitability. In hexamethonium, the amplitude of the sEPSP was significantly greater in MI ICNs. In conclusion, we identify a important role of M‐current in the regulation of the excitability of porcine ICNs, and demonstrate enhanced membrane depolarization of ICNs from MI animals after presynaptic stimulation due, in part, to greater inhibition of IM during tetanic nerve stimulation which may underlie the enhanced sensitivity to VNS in MI pigs.Support or Funding InformationThis work was supported in part by NIH grant OT2OD023848.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

How does transient signaling input affect the spike timing of postsynaptic neuron near the threshold regime: an analytical study

The noisy threshold regime, where even a small set of presynaptic neurons can significantly affect postsynaptic spike-timing, is suggested as a key requisite for computation in neurons with high variability. It also has been proposed that signals under the noisy conditions are successfully transferred by a few strong synapses and/or by an assembly of nearly synchronous synaptic activities. We analytically investigate the impact of a transient signaling input on a leaky integrate-and-fire postsynaptic neuron that receives background noise near the threshold regime. The signaling input models a single strong synapse or a set of synchronous synapses, while the background noise represents a lot of weak synapses. We find an analytic solution that explains how the first-passage time (ISI) density is changed by transient signaling input. The analysis allows us to connect properties of the signaling input like spike timing and amplitude with postsynaptic first-passage time density in a noisy environment. Based on the analytic solution, we calculate the Fisher information with respect to the signaling input’s amplitude. For a wide range of amplitudes, we observe a non-monotonic behavior for the Fisher information as a function of background noise. Moreover, Fisher information non-trivially depends on the signaling input’s amplitude; changing the amplitude, we observe one maximum in the high level of the background noise. The single maximum splits into two maximums in the low noise regime. This finding demonstrates the benefit of the analytic solution in investigating signal transfer by neurons.

Sleep on it.

Evidence of sleep-induced weakening of synapses lends support for a controversial hypothesis

Glucocorticoids activate a synapse weakening pathway culminating in tau phosphorylation in the hippocampus

Evidence suggests that the stress hormones glucocorticoids (GCs) can cause cognitive deficits and neurodegeneration. Previous studies have found GCs facilitate physiological synapse weakening, termed long-term depression (LTD), though the precise mechanisms underlying this are poorly understood. Here we show that GCs activate glycogen synthase kinase-3 (GSK-3), a kinase crucial to synapse weakening signals. Critically, this ultimately leads to phosphorylation of the microtubule associated protein tau, specifically at the serine 396 residue, and this is a causal factor in the GC-mediated impairment of synaptic function. These findings reveal the link between GCs and synapse weakening signals, and the potential for stress-induced priming of neurodegeneration. This could have important implications for our understanding of how stress can lead to neurodegenerative disease.

Homer1a drives homeostatic scaling-down of excitatory synapses during sleep.

Sleep is an essential process that supports learning and memory by acting on synapses through poorly understood molecular mechanisms. Using biochemistry, proteomics, and imaging in mice, we find that during sleep, synapses undergo widespread alterations in composition and signaling, including weakening of synapses through removal and dephosphorylation of synaptic AMPA-type glutamate receptors. These changes are driven by the immediate early gene Homer1a and signaling from group I metabotropic glutamate receptors mGluR1/5. Homer1a serves as a molecular integrator of arousal and sleep need via the wake- and sleep-promoting neuromodulators, noradrenaline and adenosine, respectively. Our data suggest that homeostatic scaling-down, a global form of synaptic plasticity, is active during sleep to remodel synapses and participates in the consolidation of contextual memory.

Ultrastructural evidence for synaptic scaling across the wake/sleep cycle.

It is assumed that synaptic strengthening and weakening balance throughout learning to avoid runaway potentiation and memory interference. However, energetic and informational considerations suggest that potentiation should occur primarily during wake, when animals learn, and depression should occur during sleep. We measured 6920 synapses in mouse motor and sensory cortices using three-dimensional electron microscopy. The axon-spine interface (ASI) decreased ~18% after sleep compared with wake. This decrease was proportional to ASI size, which is indicative of scaling. Scaling was selective, sparing synapses that were large and lacked recycling endosomes. Similar scaling occurred for spine head volume, suggesting a distinction between weaker, more plastic synapses (~80%) and stronger, more stable synapses. These results support the hypothesis that a core function of sleep is to renormalize overall synaptic strength increased by wake.

Analytical Calculation of Mutual Information between Weakly Coupled Poisson-Spiking Neurons in Models of Dynamically Gated Communication.

Mutual information is a commonly used measure of communication between neurons, but little theory exists describing the relationship between mutual information and the parameters of the underlying neuronal interaction. Such a theory could help us understand how specific physiological changes affect the capacity of neurons to synaptically communicate, and, in particular, they could help us characterize the mechanisms by which neuronal dynamics gate the flow of information in the brain. Here we study a pair of linear-nonlinear-Poisson neurons coupled by a weak synapse. We derive an analytical expression describing the mutual information between their spike trains in terms of synapse strength, neuronal activation function, the time course of postsynaptic currents, and the time course of the background input received by the two neurons. This expression allows mutual information calculations that would otherwise be computationally intractable. We use this expression to analytically explore the interaction of excitation, information transmission, and the convexity of the activation function. Then, using this expression to quantify mutual information in simulations, we illustrate the information-gating effects of neural oscillations and oscillatory coherence, which may either increase or decrease the mutual information across the synapse depending on parameters. Finally, we show analytically that our results can quantitatively describe the selection of one information pathway over another when multiple sending neurons project weakly to a single receiving neuron.

Whisker Deprivation Drives Two Phases of Inhibitory Synapse Weakening in Layer 4 of Rat Somatosensory Cortex.

Inhibitory synapse development in sensory neocortex is experience-dependent, with sustained sensory deprivation yielding fewer and weaker inhibitory synapses. Whether this represents arrest of synapse maturation, or a more complex set of processes, is unclear. To test this, we measured the dynamics of inhibitory synapse development in layer 4 of rat somatosensory cortex (S1) during continuous whisker deprivation from postnatal day 7, and in age-matched controls. In deprived columns, spontaneous miniature inhibitory postsynaptic currents (mIPSCs) and evoked IPSCs developed normally until P15, when IPSC amplitude transiently decreased, recovering by P16 despite ongoing deprivation. IPSCs remained normal until P22, when a second, sustained phase of weakening began. Delaying deprivation onset by 5 days prevented the P15 weakening. Both early and late phase weakening involved measurable reduction in IPSC amplitude relative to prior time points. Thus, deprivation appears to drive two distinct phases of active IPSC weakening, rather than simple arrest of synapse maturation.

Interplay between Subthreshold Oscillations and Depressing Synapses in Single Neurons.

In this paper we analyze the interplay between the subthreshold oscillations of a single neuron conductance-based model and the short-term plasticity of a dynamic synapse with a depressing mechanism. In previous research, the computational properties of subthreshold oscillations and dynamic synapses have been studied separately. Our results show that dynamic synapses can influence different aspects of the dynamics of neuronal subthreshold oscillations. Factors such as maximum hyperpolarization level, oscillation amplitude and frequency or the resulting firing threshold are modulated by synaptic depression, which can even make subthreshold oscillations disappear. This influence reshapes the postsynaptic neuron’s resonant properties arising from subthreshold oscillations and leads to specific input/output relations. We also study the neuron’s response to another simultaneous input in the context of this modulation, and show a distinct contextual processing as a function of the depression, in particular for detection of signals through weak synapses. Intrinsic oscillations dynamics can be combined with the characteristic time scale of the modulatory input received by a dynamic synapse to build cost-effective cell/channel-specific information discrimination mechanisms, beyond simple resonances. In this regard, we discuss the functional implications of synaptic depression modulation on intrinsic subthreshold dynamics.

The Rag-Ragulator Complex Regulates Lysosome Function and Phagocytic Flux in Microglia.

Microglia are resident macrophages of the CNS that are essential for phagocytosis of apoptotic neurons and weak synapses during development. We show that RagA and Lamtor4, two components of the Rag-Ragulator complex, are essential regulators of lysosomes in microglia. In zebrafish lacking RagA function, microglia exhibit an expanded lysosomal compartment, but they are unable to properly digest apoptotic neuronal debris. Previous biochemical studies have placed the Rag-Ragulator complex upstream of mTORC1 activation in response to cellular nutrient availability. Nonetheless, RagA and mTOR mutant zebrafish have distinct phenotypes, indicating that the Rag-Ragulator complex has functions independent of mTOR signaling. Our analysis reveals an essential role of the Rag-Ragulator complex in proper lysosome function and phagocytic flux in microglia.

Activation of a synapse weakening pathway by human Val66 but not Met66 pro-brain-derived neurotrophic factor (proBDNF)

This study describes a fundamental functional difference between the two main polymorphisms of the pro-form of brain-derived neurotrophic factor (proBDNF), providing an explanation as to why these forms have such different age-related neurological outcomes. Healthy young carriers of the Met66 form (present in ∼30% Caucasians) have reduced hippocampal volume and impaired hippocampal-dependent memory function, yet the same polymorphic population shows enhanced cognitive recovery after traumatic brain injury, delayed cognitive dysfunction during aging, and lower risk of late-onset Alzheimer’s disease (AD) compared to those with the more common Val66 polymorphism. To examine the differences between the protein polymorphisms in structure, kinetics of binding to proBDNF receptors and in vitro function, we generated purified cleavage-resistant human variants. Intriguingly, we found no statistical differences in those characteristics. As anticipated, exogenous application of proBDNF Val66 to rat hippocampal slices dysregulated synaptic plasticity, inhibiting long-term potentiation (LTP) and facilitating long-term depression (LTD). We subsequently observed that this occurred via the glycogen synthase kinase 3β (GSK3β) activation pathway. However, surprisingly, we found that Met66 had no such effects on either LTP or LTD. These novel findings suggest that, unlike Val66, the Met66 variant does not facilitate synapse weakening signaling, perhaps accounting for its protective effects with aging.

Columnar architecture improves noise robustness in a model cortical network.

Cortical columnar architecture was discovered decades ago yet there is no agreed upon explanation for its function. Indeed, some have suggested that it has no function, it is simply an epiphenomenon of developmental processes. To investigate this problem we have constructed a computer model of one square millimeter of layer 2/3 of the primary visual cortex (V1) of the cat. Model cells are connected according to data from recent paired cell studies, in particular the connection probability between pyramidal cells is inversely proportional both to the distance separating the cells and to the distance between the preferred parameters (features) of the cells. We find that these constraints, together with a columnar architecture, produce more tightly clustered populations of cells when compared to the random architecture seen in, for example, rodents. This causes the columnar network to converge more quickly and accurately on the pattern representing a particular stimulus in the presence of noise, suggesting that columnar connectivity functions to improve pattern recognition in cortical circuits. The model also suggests that synaptic failure, a phenomenon exhibited by weak synapses, may conserve metabolic resources by reducing transmitter release at these connections that do not contribute to network function.

Dynamic control of 26S proteasome function at CNS synapses (478.3)

The selective strengthening and weakening of synapses in response to past experience and activity is known as synaptic plasticity and is fundamental to all brain processes such as the ability to learn, form memories and modify behavior. In contrast, impairments in synaptic plasticity are considered to contribute to neuropsychiatric disorders and neurodegenerative diseases. Synaptic plasticity is largely mediated by both morphological and functional modifications to synapses. Local protein synthesis and protein degradation are known to contribute to these modifications. It is now clear that regulated proteolysis via the ubiquitin proteasome system (UPS) plays a major role in the growth and development, maintenance and remodeling of synaptic connections in the brain. We and others have previously found a novel form of regulation for the 26S proteasome in neurons involving the plasticity kinase Ca2+/calmodulin‐dependent protein kinases II alpha (CaMKIIα). CaMKIIα phosphorylates the ATPase 19S regulatory particle (RP) subunit, Rpt6, at serine 120 (S120) in an activity‐dependent fashion to modulate the activity and control the distribution of proteasomes in neurons (Djakovic et al., 2009; 2012; Bingol et al., 2010). We find that Rpt6 phosphorylation and proteasome function regulates synaptic strength and activity‐dependent generation of dendritic spines (Djakovic et al., 2012; Hamilton et al., 2012). I will discuss our more recent work and the functional relevance of proteasome phosphorylation in neurons using newly generated Rpt6 Ser120Ala and Ser120Asp (phospho‐dead and phospho‐mimetic, respectively) genetically modified mice.

Untangling the two-way signalling route from synapses to the nucleus, and from the nucleus back to the synapses

During learning and memory, it has been suggested that the coordinated electrical activity of hippocampal neurons translates information about the external environment into internal neuronal representations, which then are stored initially within the hippocampus and subsequently into other areas of the brain. A widely held hypothesis posits that synaptic plasticity is a key feature that critically modulates the triggering and the maintenance of such representations, some of which are thought to persist over time as traces or tags. However, the molecular and cell biological basis for these traces and tags has remained elusive. Here, we review recent findings that help clarify some of the molecular and cellular mechanisms critical for these events, by untangling a two-way signalling crosstalk route between the synapses and the neuronal soma. In particular, a detailed interrogation of the soma-to-synapse delivery of immediate early gene product Arc/Arg3.1, whose induction is triggered by heightened synaptic activity in many brain areas, teases apart an unsuspected 'inverse' synaptic tagging mechanism that likely contributes to maintaining the contrast of synaptic weight between strengthened and weak synapses within an active ensemble.

Spike-timing computation properties of a feed-forward neural network model

Brain function is characterized by dynamical interactions among networks of neurons. These interactions are mediated by network topology at many scales ranging from microcircuits to brain areas. Understanding how networks operate can be aided by understanding how the transformation of inputs depends upon network connectivity patterns, e.g., serial and parallel pathways. To tractably determine how single synapses or groups of synapses in such pathways shape these transformations, we modeled feed-forward networks of 7–22 neurons in which synaptic strength changed according to a spike-timing dependent plasticity (STDP) rule. We investigated how activity varied when dynamics were perturbed by an activity-dependent electrical stimulation protocol (spike-triggered stimulation; STS) in networks of different topologies and background input correlations. STS can successfully reorganize functional brain networks in vivo, but with a variability in effectiveness that may derive partially from the underlying network topology. In a simulated network with a single disynaptic pathway driven by uncorrelated background activity, structured spike-timing relationships between polysynaptically connected neurons were not observed. When background activity was correlated or parallel disynaptic pathways were added, however, robust polysynaptic spike timing relationships were observed, and application of STS yielded predictable changes in synaptic strengths and spike-timing relationships. These observations suggest that precise input-related or topologically induced temporal relationships in network activity are necessary for polysynaptic signal propagation. Such constraints for polysynaptic computation suggest potential roles for higher-order topological structure in network organization, such as maintaining polysynaptic correlation in the face of relatively weak synapses.

RETRACTED ARTICLE: From neurons to microglia, with complements

A study in this issue of Nature Neuroscience demonstrates that astrocytic transforming growth factor-β facilitates complement-mediated removal of weak synapses by microglia during the synaptic pruning period.

Perchance to Prune

The article discusses the neurological aspects of sleep. The authors note that all animals sleep, adding that some animals, such as dolphins, have unique adaptations to accommodate sleep. Topics include the authors' synaptic homeostasis hypothesis (SHY) which suggests sleep weakens connections among nerve cells, conventional wisdom regarding sleep's role in learning and memory formation, and the link between a weakening of synapses and the amount of energy the brain consumes.

The interplay between STDP rules and anticipated synchronization in the organization of neuronal networks

Neuronal networks are able to synchronize in phase-locking regimes. Depending on the structural connectivity it is possible to determine the sign of the phase difference between oscillatory nodes. Specially in unidirectionally coupled motifs the relative phase difference is usually positive. However it has been shown that in the presence of dynamical inhibitory loops, unidirectionally coupled neuron models may present both positive or negative phase difference [1]. The unusual regime in which the phase difference is negative is called anticipated synchronization (AS) [2]. It means that two neurons or two neuronal populations coupled in a master-slave configuration can oscillate in such a way that the slave leads the master. These results are important in light of the growing experimental evidence that the synaptic strength between neurons can undergo spike-timing-dependent plasticity (STDP) [3]. In the delayed synchronization regime the master (pre-synaptic) neuron fires a spike before the slave (post-synaptic) neuron, which under STDP rules would facilitate long term potentiation (LTP), whereas in the AS regime the slave neuron fires a spike before the master neuron, contributing to long term depression (LTD) [4]. Since it has been shown previously that a simple 3-neuron motif can undergo a continuous transition from positive to negative values of relative phase via changes in synaptic conductances [1], the interplay between these regimes and STDP mechanisms is likely to play a very significant role in the organization of the system dynamics. Considering that in certain situations the relative potentiation in strong synapses is less intense than in weak synapses, but the depression do not show this dependence [5], we compare the effects of additive, multiplicative and hybrid rules in our motifs. Together with AS regimes in neuronal populations, STDP rules give synaptic weight distributions that are comparable to experiments in cortex [6,7].

Altered Synaptic Dynamics during Normal Brain Aging

What is the neuroanatomical basis for the decline in brain function that occurs during normal aging? Previous postmortem studies have blamed it on a reduction in spine density, though results remain controversial and spine dynamics were not assessed. We used chronic in vivo two-photon imaging of dendritic spines and axonal boutons in somatosensory cortex for up to 1 year in thy1 GFP mice to test the hypothesis that aging is associated with alterations in synaptic dynamics. We find that the density of spines and en passant boutons (EPBs) in pyramidal cells increases throughout adult life but is stable between mature (8-15 months) and old (>20 months) mice. However, new spines and EPBs are two to three times more likely to be stabilized over 30 d in old mice, although the long-term retention (over months) of stable spines is lower in old animals. In old mice, spines are smaller on average but are still able to make synaptic connections regardless of their size, as assessed by serial section electron microscopy reconstructions of previously imaged dendrites. Thus, our data suggest that age-related deficits in sensory perception are not associated with synapse loss in somatosensory cortex (as might be expected) but with alterations in the size and stability of spines and boutons observed in this brain area. The changes we describe here likely result in weaker synapses that are less capable of short-term plasticity in aged individuals, and therefore to less efficient circuits.