Inhibition as a Binary Switch for Excitatory Plasticity in Pyramidal Neurons

Synaptic plasticity is thought to induce memory traces in the brain that are the foundation of learning. To ensure the stability of these traces in the presence of further learning, however, a regulation of plasticity appears beneficial. Here, we take up the recent suggestion that dendritic inhibition can switch plasticity of excitatory synapses on and off by gating backpropagating action potentials (bAPs) and calcium spikes, i.e., by gating the coincidence signals required for Hebbian forms of plasticity. We analyze temporal and spatial constraints of such a gating and investigate whether it is possible to suppress bAPs without a simultaneous annihilation of the forward-directed information flow via excitatory postsynaptic potentials (EPSPs). In a computational analysis of conductance-based multi-compartmental models, we demonstrate that a robust control of bAPs and calcium spikes is possible in an all-or-none manner, enabling a binary switch of coincidence signals and plasticity. The position of inhibitory synapses on the dendritic tree determines the spatial extent of the effect and allows a pathway-specific regulation of plasticity. With appropriate timing, EPSPs can still trigger somatic action potentials, although backpropagating signals are abolished. An annihilation of bAPs requires precisely timed inhibition, while the timing constraints are less stringent for distal calcium spikes. We further show that a wide-spread motif of local circuits—feedforward inhibition—is well suited to provide the temporal precision needed for the control of bAPs. Altogether, our model provides experimentally testable predictions and demonstrates that the inhibitory switch of plasticity can be a robust and attractive mechanism, hence assigning an additional function to the inhibitory elements of neuronal microcircuits beyond modulation of excitability.     

Potentiation of mossy fiber EPSCs in the cerebellar nuclei by NMDA receptor activation followed by postinhibitory rebound current

Behavioral and computational studies predict that synaptic plasticity of excitatory mossy fiber inputs to cerebellar nuclear neurons is required for associative learning, but standard tetanization protocols fail to potentiate nuclear cell EPSCs in mouse cerebellar slices. Nuclear neurons fire action potentials spontaneously unless strongly inhibited by Purkinje neurons, raising the possibility that plasticity-triggering signals in these cells differ from those at classical Hebbian synapses. Based on predictions of neuronal activity during delay eyelid conditioning, we developed quasi-physiological induction protocols consisting of high-frequency mossy fiber stimulation and postsynaptic hyperpolarization. Robust, NMDA receptor-dependent potentiation of nuclear cell EPSCs occurred with protocols including a 150-250 ms hyperpolarization in which mossy fiber stimulation preceded a postinhibitory rebound depolarization. Mossy fiber stimulation potentiated EPSCs even when postsynaptic spiking was prevented by voltage-clamp, as long as rebound current was evoked. These data suggest that Purkinje cell inhibition guides the strengthening of excitatory synapses in the cerebellar nuclei.     

Transitory memory retrieval in a biologically plausible neural network model

A number of memory models have been proposed. These all have the basic structure that excitatory neurons are reciprocally connected by recurrent connections together with the connections with inhibitory neurons, which yields associative memory (i.e., pattern completion) and successive retrieval of memory. In most of the models, a simple mathematical model for a neuron in the form of a discrete map is adopted. It has not, however, been clarified whether behaviors like associative memory and successive retrieval of memory appear when a biologically plausible neuron model is used. In this paper, we propose a network model for associative memory and successive retrieval of memory based on Pinsky-Rinzel neurons. The state of pattern completion in associative memory can be observed with an appropriate balance of excitatory and inhibitory connection strengths. Increasing of the connection strength of inhibitory interneurons changes the state of memory retrieval from associative memory to successive retrieval of memory. We investigate this transition.     

Monosynaptic GABAergic signaling from dentate to CA3 with a pharmacological and physiological profile typical of mossy fiber synapses

Mossy fibers are the sole excitatory projection from dentate gyrus granule cells to the hippocampus, where they release glutamate, dynorphin, and zinc. In addition, mossy fiber terminals show intense immunoreactivity for the inhibitory neurotransmitter GABA. Fast inhibitory transmission at mossy fiber synapses, however, has not previously been reported. Here, we show that electrical or chemical stimuli that recruit dentate granule cells elicit monosynaptic GABA(A) receptor-mediated synaptic signals in CA3 pyramidal neurons. These inhibitory signals satisfy the criteria that distinguish mossy fiber-CA3 synapses: high sensitivity to metabotropic glutamate receptor agonists, facilitation during repetitive stimulation, and NMDA receptor-independent long-term potentiation. GABAergic transmission from the dentate gyrus to CA3 has major implications not only for information flow into the hippocampus but also for developmental and pathological processes involving the hippocampus.     

Stability of complex spike timing-dependent plasticity in cerebellar learning

Dynamics of spike-timing dependent synaptic plasticity are analyzed for excitatory and inhibitory synapses onto cerebellar Purkinje cells. The purpose of this study is to place theoretical constraints on candidate synaptic learning rules that determine the changes in synaptic efficacy due to pairing complex spikes with presynaptic spikes in parallel fibers and inhibitory interneurons. Constraints are derived for the timing between complex spikes and presynaptic spikes, constraints that result from the stability of the learning dynamics of the learning rule. Potential instabilities in the parallel fiber synaptic learning rule are found to be stabilized by synaptic plasticity at inhibitory synapses if the inhibitory learning rules are stable, and conditions for stability of inhibitory plasticity are given. Combining excitatory with inhibitory plasticity provides a mechanism for minimizing the overall synaptic input. Stable learning rules are shown to be able to sculpt simple-spike patterns by regulating the excitability of neurons in the inferior olive that give rise to climbing fibers.     

Right-left discrimination in a biologically oriented model of the cockroach escape system

We present a biologically oriented model that accounts for left-right discrimination in the cockroach's escape behavior. The model includes the main groups of neurons found to be involved in the escape response. Each one of the included neurons is described by the actual processes taking place in an individual neuron (formation of an action potential, transmitter release, conductance changes, etc.). Furthermore, realistic chemical synapses (excitatory or inhibitory and able to undergo different types of modulation) connect the various neurons. With this model, we were able to achieve, for a wide range of inputs representing different wind directions, behavior which resembles that found experimentally. The model indicates that several synaptic properties, in particular postsynaptic inhibition and presynaptic facilitation, play a key role in the discrimination of wind direction. Received: 22 January 1999 / Accepted in revised form: 1 March 1999     

A Novel Whole-Cell Mechanism for Long-Term Memory Enhancement

Olfactory-discrimination learning was shown to induce a profound long-lasting enhancement in the strength of excitatory and inhibitory synapses of pyramidal neurons in the piriform cortex. Notably, such enhancement was mostly pronounced in a sub-group of neurons, entailing about a quarter of the cell population. Here we first show that the prominent enhancement in the subset of cells is due to a process in which all excitatory synapses doubled their strength and that this increase was mediated by a single process in which the AMPA channel conductance was doubled. Moreover, using a neuronal-network model, we show how such a multiplicative whole-cell synaptic strengthening in a sub-group of cells that form a memory pattern, sub-serves a profound selective enhancement of this memory. Network modeling further predicts that synaptic inhibition should be modified by complex learning in a manner that much resembles synaptic excitation. Indeed, in a subset of neurons all GABA_A-receptors mediated inhibitory synapses also doubled their strength after learning. Like synaptic excitation, Synaptic inhibition is also enhanced by two-fold increase of the single channel conductance. These findings suggest that crucial learning induces a multiplicative increase in strength of all excitatory and inhibitory synapses in a subset of cells, and that such an increase can serve as a long-term whole-cell mechanism to profoundly enhance an existing Hebbian-type memory. This mechanism does not act as synaptic plasticity mechanism that underlies memory formation but rather enhances the response of already existing memory. This mechanism is cell-specific rather than synapse-specific; it modifies the channel conductance rather than the number of channels and thus has the potential to be readily induced and un-induced by whole-cell transduction mechanisms.     

When inhibition not excitation synchronizes neural firing

Excitatory and inhibitory synaptic coupling can have counter-intuitive effects on the synchronization of neuronal firing. While it might appear that excitatory coupling would lead to synchronization, we show that frequently inhibition rather than excitation synchronizes firing. We study two identical neurons described by integrate-and-fire models, general phase-coupled models or the Hodgkin-Huxley model with mutual, non-instantaneous excitatory or inhibitory synapses between them. We find that if the rise time of the synapse is longer than the duration of an action potential, inhibition not excitation leads to synchronized firing.     

The Role of Inhibition in an Associative Memory Model of the Olfactory Bulb

The external plexiform layer is where theinteractions between the mitral (excitatory) and granule (inhibitory)cells of the olfactory bulb (OB) take place. Two outstanding features ofthese interactions are that they aredendrodendritic and that there seem to be nonebetween excitatory cells. The latter are usually credited with the role of forming Hebbian cell assemblies.Hence, it would seem that this structure lacks the necessaryingredients for an associative memory system.In this article we show that in spite of these two properties thissystem can serve as an associative memory. Our model incorporates theessential anatomical characteristics of the OB. The memories in oursystem, defined by Hebbian mitral assemblies, are activated viathe interactions with the inhibitory granule cells. The nonlinearityis introduced in our model via a sigmoid function that describesneurotransmitter release in reciprocal dendrodendritic synapses. Thecapacity (maximal number of odors that can be memorized) depends onthe sparseness of coding that is being used. For very low memoryactivities, the capacity grows as a fractional power of the number ofneurons. We validate the theoretical results by numericalsimulations. An interesting result of our model is that its capacityincreases as a function of the ratio of inhibitory to excitatorypopulations. This may provide an explanation for the dominance ofinhibitory cells in the olfactory bulb.     

Excitatory and feed-forward inhibitory hippocampal synapses work synergistically as an adaptive filter of natural spike trains

Short-term synaptic plasticity (STP) is an important mechanism for modifying neural circuits during computation. Although STP is much studied, its role in the processing of complex natural spike patterns is unknown. Here we analyze the responses of excitatory and inhibitory hippocampal synapses to natural spike trains at near-physiological temperatures. Our results show that excitatory and inhibitory synapses express complementary sets of STP components that selectively change synaptic strength during epochs of high-frequency discharge associated with hippocampal place fields. In both types of synapses, synaptic strength rapidly alternates between a near-constant level during low activity and another near-constant, but elevated (for excitatory synapses) or reduced (for inhibitory synapses) level during high-frequency epochs. These history-dependent changes in synaptic strength are largely independent of the particular temporal pattern within the discharges, and occur concomitantly in the two types of synapses. When excitatory and feed-forward inhibitory synapses are co-activated within the hippocampal feed-forward circuit unit, the net effect of their complementary STP is an additional increase in the gain of excitatory synapses during high-frequency discharges via selective disinhibition. Thus, excitatory and feed-forward inhibitory hippocampal synapses in vitro act synergistically as an adaptive filter that operates in a switch-like manner and is selective for high-frequency epochs.     

Does inhibition balance excitation in neocortex?

The distribution of inhibitory and excitatory synapses on neocortical neurons is at odds with a simple view that cortical functioning can persist by maintaining a balance between inhibitory and excitatory drives. Pyramidal cells can potentially be shut down by very powerful proximal inhibitory synapses, despite these accounting for perhaps less than 1% of their total number of synaptic inputs. Interneurons in contrast are dominated by excitatory inputs. These may be powerful enough to effect an apparent depolarizing block at the soma. In this extreme case though, models suggest that action potentials are generated down the axon, and the cells behave like integrate-and-fire neurons. We discuss possible network implications of these modelling studies.     

Role of different voltage-gated Ca2+ channels in cortical spreading depression: specific requirement of P/Q-type Ca2+ channels

Gain-of-function mutations in CaV 2.1 (P/Q-type) Ca2+ channels cause familial hemiplegic migraine type 1 (FHM1), a subtype of migraine with aura. Knockin (KI) mice carrying FHM1 mutations show increased neuronal P/Q-type current and facilitation of induction and propagation of cortical spreading depression (CSD), the phenomenon that underlies migraine aura and may activate migraine headache mechanisms. We recently studied cortical neurotransmission in neuronal microcultures and brain slices of FHM1 KI mice, and showed (1) gain-of-function of excitatory neurotransmission, due to increased action potential-evoked Ca2+ influx and increased probability of glutamate release at pyramidal cell synapses, but unaltered inhibitory neurotransmission at fast-spiking interneuron synapses, and (2) a causative link between enhanced glutamate release and facilitation of CSD induced by brief pulses of high K+ in cortical slices. Here, we show that after blockade of either the P/Q-type Ca2+ channels or the NMDA receptors, CSD cannot be induced in wild-type mouse cortical slices. In contrast, blockade of N- or R-type Ca2+ channels has only a small inhibitory effect on CSD threshold and velocity of propagation. Our findings support a model in which Ca2+ influx through presynaptic P/Q-type Ca2+ channels with consequent release of glutamate from recurrent cortical pyramidal cell synapses and activation of NMDA receptors are required for initiation and propagation of the CSD involved in migraine.     

Calcium and facilitation at two classes of crustacean neuromuscular synapses

The closer muscle of the crab, Chionoecetes, has at least two classes of excitatory neuromuscular synapses. In one class of synapses an action potential depolarizing the synaptic region releases much more transmitter if it has been preceded recently by another action potential. The other class of synapses shows this property, called facilitation, to a far lesser extent. Immediately after one conditioning stimulus the level of facilitation is similar in both classes. The rate of the ensuing decay of the facilitation is the critical factor differentiating the two classes of synapses. The relationship between external Ca⁺⁺ concentration and transmitter release is similar for both classes of synapses. The slope of a double logarithmic plot of this relationship varies from 3.1 between 5 and 10 mM Ca⁺⁺ to 0.9 between 30 and 40 mM Ca⁺⁺. Facilitation does not significantly change when tested in external Ca⁺⁺ concentrations ranging from 7 to 30 mM. The extracellularly recorded nerve terminal action potential does not increase in amplitude during facilitation. The results suggest that the mechanism of synaptic facilitation is similar for both classes of synapses and occurs after the stage in transmitter release involving Ca⁺⁺.     

Synaptic development in the crayfish opener muscle

Nerve terminal regions in walking leg opener muscles of several crayfish of different ages (0 to 245 days after hatching) were examined by means of electron microscopy. This muscle is innervated by two axons (excitatory and inhibitory) and at maturity contains three classes of synapse: excitatory and inhibitory neuromuscular synapses, and inhibitory axo-axonal synapses. The muscle itself is initially a syncytium, which gradually becomes subdivided into distinct “muscle fibers” as the animal matures. Innervation was not found in the opener muscle just before or just after hatching, but was present in restricted locations on the inner side of the muscle within a few days of hatching. As the muscle enlarged and became subdivided, innervation appeared in various other locations. Synaptic contacts were located in young stages soon after hatching, and in later stages. Morphological differences characteristic of excitatory and inhibitory nerve terminals could be found even at the earliest stages of innervation. Both excitatory and inhibitory synapses, but particularly the former, showed evidence of progressive enlargement to a final size within the first two months, and no evidence for further enlargement of existing synapses thereafter. Synaptic maturation also involved the appearance of presynaptic “dense bodies” thought to be regions at which transmitter substance is preferentially released. Nerve terminals at different levels of maturation were observed in opener muscles of young crayfish. Clear evidence for differential maturation of the three types of synapse present in this muscle was obtained. The inhibitory neuromuscular synapses attained their final average size and developed their dense bodies sooner than the excitatory neuromuscular synapses. The inhibitory axo-axonal synapses were the last to appear and to mature.     

A structural model for phosphorylation control of Dictyostelium myosin II thick filament assembly

Deletion of the synapsin I genes, encoding one of the major groups of proteins on synaptic vesicles, in mice causes late onset epileptic seizures and enhanced experimental temporal lobe epilepsy. However, mice lacking synapsin I maintain normal excitatory synaptic transmission and modulation but for an enhancement of paired-pulse facilitation. To elucidate the cellular basis for epilepsy in mutants, we examined whether the inhibitory synapses in the hippocampus from mutant mice are intact by electrophysiological and morphological means. In the cultured hippocampal synapses from mutant mice, repeated application of a hypertonic solution significantly suppressed the subsequent transmitter release, associated with an accelerated vesicle replenishing time at the inhibitory synapses, compared with the excitatory synapses. In the mutants, morphologically identifiable synaptic vesicles failed to accumulate after application of a hypertonic solution at the inhibitory preterminals but not at the excitatory preterminals. In the CA3 pyramidal cells in hippocampal slices from mutant mice, inhibitory postsynaptic currents evoked by direct electrical stimulation of the interneuron in the striatum oriens were characterized by reduced quantal content compared with those in wild type. We conclude that synapsin I contributes to the anchoring of synaptic vesicles, thereby minimizing transmitter depletion at the inhibitory synapses. This may explain, at least in part, the epileptic seizures occurring in the synapsin I mutant mice.     

PKMζ Inhibition Reverses Learning-Induced Increases in Hippocampal Synaptic Strength and Memory during Trace Eyeblink Conditioning

A leading candidate in the process of memory formation is hippocampal long-term potentiation (LTP), a persistent enhancement in synaptic strength evoked by the repetitive activation of excitatory synapses, either by experimental high-frequency stimulation (HFS) or, as recently shown, during actual learning. But are the molecular mechanisms for maintaining synaptic potentiation induced by HFS and by experience the same? Protein kinase Mzeta (PKMζ), an autonomously active atypical protein kinase C isoform, plays a key role in the maintenance of LTP induced by tetanic stimulation and the storage of long-term memory. To test whether the persistent action of PKMζ is necessary for the maintenance of synaptic potentiation induced after learning, the effects of ZIP (zeta inhibitory peptide), a PKMζ inhibitor, on eyeblink-conditioned mice were studied. PKMζ inhibition in the hippocampus disrupted both the correct retrieval of conditioned responses (CRs) and the experience-dependent persistent increase in synaptic strength observed at CA3-CA1 synapses. In addition, the effects of ZIP on the same associative test were examined when tetanic LTP was induced at the hippocampal CA3-CA1 synapse before conditioning. In this case, PKMζ inhibition both reversed tetanic LTP and prevented the expected LTP-mediated deleterious effects on eyeblink conditioning. Thus, PKMζ inhibition in the CA1 area is able to reverse both the expression of trace eyeblink conditioned memories and the underlying changes in CA3-CA1 synaptic strength, as well as the anterograde effects of LTP on associative learning.     

Neuromuscular synapses on the dactyl opener muscle of the lobster Homarus americanus

The crustacean dactyl opener neuromuscular system has been studied extensively as a model system that exhibits several forms of synaptic plasticity. We report the ultrastructural features of the synapses on dactyl opener of the lobster (Homarus americanus) as determined by examination of serial thin sections. Several innervation sites supplied by an inhibitory motoneuron have been observed without nearby excitatory innervation, indicating that excitatory and inhibitory inputs to the muscle are not always closely matched. The ultrastructural features of the lobster synapses are generally similar to those described previously for the homologous crayfish muscle, with one major distinction: few dense bars are seen at the presynaptic membranes of these lobster synapses. The majority of the lobster neuromuscular synapses lack dense bars altogether, and the mean number of dense bars per synapse is relatively low. In view of the finding that the physiology of the lobster dactyl opener synapses is similar to that reported for crayfish, these ultrastructural observations suggest that the structural complexity of the synapses may not be a critical factor determining synaptic plasticity.This work was supported by funds from the University of Virginia Research and Development Committee.     

A neural network model of the cerebellar cortex performing dynamic associations

The present paper proposes a model which applies formal neural network modeling techniques to construct a theoretical representation of the cerebellar cortex and its performances in motor control. A schema that makes explicit use of propagation delays of neural signals, is introduced to describe the ability to store temporal sequences of patterns in the Golgi-granule cell system. A perceptron association is then performed on these sequences of patterns by the Purkinje cell layer. The model conforms with important biological constraints, such as the known excitatory or inhibitory nature of the various synapses. Also, as suggested by experimental evidence, the synaptic plasticity underlying the learning ability of the model, is confined to the parallel fiber — Purkinje cell synapses, and takes place under the control of the climbing fibers. The result is a neural network model, constructed according to the anatomy of the cerebellar cortex, and capable of learning and retrieval of temporal sequences of patterns. It provides a framework to represent and interpret properties of learning and control of movements by the cerebellum, and to assess the capacity of formal neural network techniques for modeling of real neural systems.     

Neurotransmission: emerging roles of endocannabinoids

Postsynaptic release of endocannabinoids can inhibit presynaptic neurotransmitter release on short and long timescales. This retrograde inhibition occurs at both excitatory and inhibitory synapses and may provide a mechanism for synaptic gain control, short-term associative plasticity, reduction of synaptic crosstalk, and metaplasticity.