Principles governing the operation of synaptic inhibition in dendrites

Synaptic inhibition plays a key role in shaping the dynamics of neuronal networks and selecting cell assemblies. Typically, an inhibitory axon contacts a particular dendritic subdomain of its target neuron, where it often makes 10-20 synapses, sometimes on very distal branches. The functional implications of such a connectivity pattern are not well understood. Our experimentally based theoretical study highlights several new and counterintuitive principles for dendritic inhibition. We show that distal "off-path" rather than proximal "on-path" inhibition effectively dampens proximal excitable dendritic "hotspots," thus powerfully controlling the neuron's output. Additionally, with multiple synaptic contacts, inhibition operates globally, spreading centripetally hundreds of micrometers from the inhibitory synapses. Consequently, inhibition in regions lacking inhibitory synapses may exceed that at the synaptic sites themselves. These results offer new insights into the synergetic effect of dendritic inhibition in controlling dendritic excitability and plasticity and in dynamically molding functional dendritic subdomains and their output.     

Endocannabinoid-mediated metaplasticity in the hippocampus

Repetitive activation of glutamatergic fibers that normally induces long-term potentiation (LTP) at excitatory synapses in the hippocampus also triggers long-term depression at inhibitory synapses (I-LTD) via retrograde endocannabinoid signaling. Little is known, however, about the physiological significance of I-LTD. Here, we show that synaptic-driven release of endocannabinoids is a highly localized and efficient process that strongly depresses cannabinoid-sensitive inhibitory inputs within the dendritic compartment of CA1 pyramidal cells. By removing synaptic inhibition in a restricted area of the dendritic tree, endocannabinoids selectively "primed" nearby excitatory synapses, thereby facilitating subsequent induction of LTP. This induction of local metaplasticity is a novel mechanism by which endocannabinoids can contribute to the storage of information in the brain.     

HCN1 channels constrain synaptically evoked Ca2+ spikes in distal dendrites of CA1 pyramidal neurons

HCN1 hyperpolarization-activated cation channels act as an inhibitory constraint of both spatial learning and synaptic integration and long-term plasticity in the distal dendrites of hippocampal CA1 pyramidal neurons. However, as HCN1 channels provide an excitatory current, the mechanism of their inhibitory action remains unclear. Here we report that HCN1 channels also constrain CA1 distal dendritic Ca2+ spikes, which have been implicated in the induction of LTP at distal excitatory synapses. Our experimental and computational results indicate that HCN1 channels provide both an active shunt conductance that decreases the temporal integration of distal EPSPs and a tonic depolarizing current that increases resting inactivation of T-type and N-type voltage-gated Ca2+ channels, which contribute to the Ca2+ spikes. This dual mechanism may provide a general means by which HCN channels regulate dendritic excitability.     

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.     

Microglial MERTK eliminates phosphatidylserine‐displaying inhibitory post‐synapses

Glia contribute to synapse elimination through phagocytosis in the central nervous system. Despite the important roles of this process in development and neurological disorders, the identity and regulation of the "eat‐me" signal that initiates glia‐mediated phagocytosis of synapses has remained incompletely understood. Here, we generated conditional knockout mice with neuronal‐specific deletion of the flippase chaperone Cdc50a, to induce stable exposure of phosphatidylserine, a well‐known "eat‐me" signal for apoptotic cells, on the neuronal outer membrane. Surprisingly, acute Cdc50a deletion in mature neurons causes preferential phosphatidylserine exposure in neuronal somas and specific loss of inhibitory post‐synapses without effects on other synapses, resulting in abnormal excitability and seizures. Ablation of microglia or the deletion of microglial phagocytic receptor Mertk prevents the loss of inhibitory post‐synapses and the seizure phenotype, indicating that microglial phagocytosis is responsible for inhibitory post‐synapse elimination. Moreover, we found that phosphatidylserine is used for microglia‐mediated pruning of inhibitory post‐synapses in normal brains, suggesting that phosphatidylserine serves as a general "eat‐me" signal for inhibitory post‐synapse elimination.     

A Model for Responses to Activation by Axodendritic Synapses

A simple mathematical model of synaptic activation shows that the response to synaptic activation depends inversely on the size of the subsynaptic process. This provides a theoretical foundation for: the relationship between excitability and cell size; a possible source of plasticity in nerve cell behavior; and the hypothesis that postsynaptic responses to activation at axodendritic synapses are of large amplitude. The last-mentioned idea provides for flexible nonlinear interaction in dendritic regions because the diminution of postsynaptic potentials (PSPs) by prior potential becomes significant at high levels of depolarization. Digital-computer simulations of nerve cell input-output behavior for axodendritic activation based on these ideas reveal: frequency-transfer curves for axodendritic activation saturate; activations combined on different dendritic branches sum approximately linearly while those on the same branch occlude; simultaneous activation of several synapses on a previously inactive dendritic branch results in a large “peak” response at the onset of stimulation; and such an initial peak may be markedly mitigated by a prior depolarization of the branch. The third-mentioned finding may represent a widespread mode of hypersensitivity to stimulus onset in neural systems and in particular may contribute to the “on” responses of sensory channels, and the fourth suggests that depolarizing synapses at extreme peripheries of dendritic fibers might in some cases serve an inhibitory function.     

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.     

Deafening drives cell-type-specific changes to dendritic spines in a sensorimotor nucleus important to learned vocalizations

Hearing loss prevents vocal learning and causes learned vocalizations to deteriorate, but how vocalization-related auditory feedback acts on neural circuits that control vocalization remains poorly understood. We deafened adult zebra finches, which rely on auditory feedback to maintain their learned songs, to test the hypothesis that deafening modifies synapses on neurons in a sensorimotor nucleus important to song production. Longitudinal in vivo imaging revealed that deafening selectively decreased the size and stability of dendritic spines on neurons that provide input to a striatothalamic pathway important to audition-dependent vocal plasticity, and changes in spine size preceded and predicted subsequent vocal degradation. Moreover, electrophysiological recordings from these neurons showed that structural changes were accompanied by functional weakening of both excitatory and inhibitory synapses, increased intrinsic excitability, and changes in spontaneous action potential output. These findings shed light on where and how auditory feedback acts within sensorimotor circuits to shape learned vocalizations.     

Clustered dynamics of inhibitory synapses and dendritic spines in the adult neocortex

A key feature of the mammalian brain is its capacity to adapt in response to experience, in part by remodeling of synaptic connections between neurons. Excitatory synapse rearrangements have been monitored in vivo by observation of dendritic spine dynamics, but lack of a vital marker for inhibitory synapses has precluded their observation. Here, we simultaneously monitor in vivo inhibitory synapse and dendritic spine dynamics across the entire dendritic arbor of pyramidal neurons in the adult mammalian cortex using large-volume, high-resolution dual-color two-photon microscopy. We find that inhibitory synapses on dendritic shafts and spines differ in their distribution across the arbor and in their remodeling kinetics during normal and altered sensory experience. Further, we find inhibitory synapse and dendritic spine remodeling to be spatially clustered and that clustering is influenced by sensory input. Our findings provide in vivo evidence for local coordination of inhibitory and excitatory synaptic rearrangements.     

Dynamic stabilization: Structural plasticity at inhibitory postsynaptic sites

Rearrangement of molecular structures at individual synapses can contribute to network plasticity. At mossy fiber presynaptic terminals, experience regulates both connectivity and structure of individual boutons. Moreover, dendritic spines and postsynaptic densities of glutamatergic synapses rapidly form and remodel in an activity-dependent manner. Recent studies of the postsynaptic scaffold molecule gephyrin have now revealed that also inhibitory shaft synapses undergo rapid remodeling at the postsynaptic scaffold level. Taking into account that also surface membrane receptors are highly mobile, local coincidence of receptors and scaffold elements in adjacent layers at dendritic shafts might depend on regulatory processes underlying synaptic plasticity.     

Inhibitory Control of Linear and Supralinear Dendritic Excitation in CA1 Pyramidal Neurons

The transformation of dendritic excitatory synaptic inputs to axonal action potential output is the fundamental computation performed by all principal neurons. We show that in the hippocampus this transformation is potently controlled by recurrent inhibitory microcircuits. However, excitatory input on highly excitable dendritic branches could resist inhibitory?control by generating strong dendritic spikes and?trigger precisely timed action potential output. Furthermore, we show that inhibition-sensitive branches can be transformed into inhibition-resistant, strongly spiking branches by intrinsic plasticity of branch excitability. In addition, we demonstrate that the inhibitory control of spatially defined dendritic excitation is strongly regulated by network activity patterns. Our findings suggest that dendritic spikes may serve to transform correlated branch input into reliable and temporally precise output even in the presence of inhibition.     

Pyramidal neurons: dendritic structure and synaptic integration

Pyramidal neurons are characterized by their distinct apical and basal dendritic trees and the pyramidal shape of their soma. They are found in several regions of the CNS and, although the reasons for their abundance remain unclear, functional studies--especially of CA1 hippocampal and layer V neocortical pyramidal neurons--have offered insights into the functions of their unique cellular architecture. Pyramidal neurons are not all identical, but some shared functional principles can be identified. In particular, the existence of dendritic domains with distinct synaptic inputs, excitability, modulation and plasticity appears to be a common feature that allows synapses throughout the dendritic tree to contribute to action-potential generation. These properties support a variety of coincidence-detection mechanisms, which are likely to be crucial for synaptic integration and plasticity.     

PTX-induced hyperexcitability affects dendritic shape and GABAergic synapse density but not synapse distribution during <Emphasis Type="Italic">Manduca</Emphasis> postembryonic motoneuron development

During the metamorphosis of the holometabolous insect, Manduca sexta, the postembryonic acquisition of adult specific motor behaviors is accompanied by changes in dendritic architecture, membrane currents, and input synapses of identified motoneurons. This study aims to test whether increased activity affects dendritic architecture and sub-dendritic input synapse distribution of the identified flight motoneuron 5 (MN5). Systemic injections of the chloride channel blocker, picrotoxin (PTX), during early pupal stages increase pupal reflex responsiveness, but overall development is not impaired. MN5 input resistance, resting membrane potential, and spiking threshold are not affected. Bath application of PTX to isolated ventral nerve cords evokes spiking in pupal and adult flight motoneurons. Quantitative three-dimensional reconstructions of the dendritic tree of the adult MN5 show that systemic PTX injections into early pupae cause dendritic overgrowth and reduce the density of GABAergic inputs. In contrast, the distribution patterns of GABAergic terminals throughout the dendritic tree remain unaltered. This indicates that increased overall excitability might cause dendritic overgrowth and decreased inhibitory input during postembryonic motoneuron remodeling, whereas sub-dendritic synapse targeting might be controlled by activity-independent signals. Behavioral testing reveals that these neuronal changes do not impede the animal’s ability to fly, but impair maximum flight performance.     

Remote Modulation of Current Transfer from Dendritic Glutamatergic Synapses by GABA-ergic Synapses of the Somatic Zone of Motoneurons: a Simulation Study

Until now, information concerning spatial interaction of postsynaptic excitation and inhibition in neuronal dendrites remains rather limited. In model experiments, we studied spatial effects of tonic co-activation of GABA-ergic synapses situated on the soma and axon hillock of a motoneuron and dendritic glutamatergic synapses with receptors sensitive or insensitive to N-methyl-D-aspartate. We analyzed distribution maps of the transmembrane potentials and excitatory currents transferred toward the soma over the reconstructed dendritic arborization of a rat abducens motoneuron (three-dimensional reconstruction). In the motoneuron, isolated tonic excitation of glutamatergic synapses induced two stable states of low (downstate) or high (upstate) spatially heterogeneous dendritic depolarization, which decayed with unequal rates along different dendritic paths. In this case, the local steady-state current-voltage relation of the dendritic membrane became N-shaped due to a limb of the negative slope within a certain voltage range. The upstate corresponding to plateau potentials associated with stereotyped motor activity patterns was analyzed in detail. In this state, most proximal dendritic sites were the main sources of the excitatory current reaching the soma, while the contribution from distal sites was negligible. Co-activation of GABA-synapses located at the soma and axon hillock reduced this depolarization and shifted the main excitatory current source from a perisomatic location to the middle, structurally more complex, region of the dendritic arborization. The more remote dendritic region having a greater membrane area and receiving a greater number of synaptic contacts became directly involved in the supply of the trigger zone by the excitatory current. We suggest that a special, not described earlier, operational mechanism of postsynaptic inhibition is manifested in the above spatial effects of activation of strategically located inhibitory synapses, and that the list of known crucial inhibitory mechanisms (namely hyperpolarization and shunting of the postsynaptic membrane) must be expanded.     

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.     

Kainate receptors differentially regulate release at two parallel fiber synapses

Presynaptic kainate receptors (KARs) facilitate or depress transmitter release at several synapses in the CNS. Here, we report that synaptically activated KARs presynaptically facilitate and depress transmission at parallel fiber synapses in the cerebellar cortex. Low-frequency stimulation of parallel fibers facilitates synapses onto both stellate cells and Purkinje cells, whereas high-frequency stimulation depresses stellate cell synapses but continues to facilitate Purkinje cell synapses. These effects are mimicked by exogenous KAR agonists and eliminated by blocking KARs. This differential frequency-dependent sensitivity of these two synapses regulates the balance of excitatory and inhibitory input to Purkinje cells and therefore their excitability.     

Synaptic dendritic activity modulates the single synaptic event

Synaptic transmission is the key system for the information transfer and elaboration among neurons. Nevertheless, a synapse is not a standing alone structure but it is a part of a population of synapses inputting the information from several neurons on a specific area of the dendritic tree of a single neuron. This population consists of excitatory and inhibitory synapses the inputs of which drive the postsynaptic membrane potential in the depolarizing (excitatory synapses) or depolarizing (inhibitory synapses) direction modulating in such a way the postsynaptic membrane potential. The postsynaptic response of a single synapse depends on several biophysical factors the most important of which is the value of the membrane potential at which the response occurs. The concurrence in a specific time window of inputs by several synapses located in a specific area of the dendritic tree can, consequently, modulate the membrane potential such to severely influence the single postsynaptic response. The degree of modulation operated by the synaptic population depends on the number of synapses active, on the relative proportion between excitatory and inbibitory synapses belonging to the population and on their specific mean firing frequencies. In the present paper we show results obtained by the simulation of the activity of a single Glutamatergic excitatory synapse under the influence of two different populations composed of the same proportion of excitatory and inhibitory synapses but having two different sizes (total number of synapses). The most relevant conclusion of the present simulations is that the information transferred by the single synapse is not and independent simple transition between a pre- and a postsynaptic neuron but is the result of the cooperation of all the synapses which concurrently try to transfer the information to the postsynaptic neuron in a given time window. This cooperativeness is mainly operated by a simple mechanism of modulation of the postsynaptic membrane potential which influences the amplitude of the different components forming the postsynaptic excitatory response.     

A GABAergic inhibitory microcircuit controlling cholinergic outflow to the airways.

GABA is the main inhibitory neurotransmitter that participates in the regulation of cholinergic outflow to the airways. We have tested the hypothesis that a monosynaptic GABAergic circuit modulates the output of airway-related vagal preganglionic neurons (AVPNs) in the rostral nucleus ambiguus by using a dual-labeling electron microscopic method combining immunocytochemistry for glutamic acid decarboxylase (GAD) with retrograde tracing from the trachea. We also determined the effects of blockade of GABAA receptors on airway smooth muscle tone. The results showed that retrogradely labeled AVPNs received a significant GAD-immunoreactive (GAD-IR) terminal input. Out of a pooled total of 3,161 synaptic contacts with retrogradely labeled somatic and dendritic profiles, 20.2% were GAD-IR. GAD-IR terminals formed significantly more axosomatic synapses than axodendritic synapses (P < 0.02). A dense population of GABAergic synaptic contacts on AVPNs provides a morphological basis for potent physiological effects of GABA on the excitability of AVPNs. GAD-IR terminals formed exclusively symmetric synaptic specializations. GAD-IR terminals were significantly larger (P < 0.05) in both length and width than unlabeled terminals synapsing on AVPNs. Therefore, the structural characteristics of certain nerve terminals may be closely correlated with their function. Pharmacological blockade of GABAA receptors within the rostral nucleus ambiguus increased activity of putative AVPNs and airway smooth muscle tone. We conclude that a tonically active monosynaptic GABAergic circuit utilizing symmetric synapses regulates the discharge of AVPNs.     

The influences of somatic and dendritic inhibition on bursting patterns in a neuronal circuit model

The balance between inhibition and excitation plays a crucial role in the generation of synchronous bursting activity in neuronal circuits. In human and animal models of epilepsy, changes in both excitatory and inhibitory synaptic inputs are known to occur. Locations and distribution of these excitatory and inhibitory synaptic inputs on pyramidal cells play a role in the integrative properties of neuronal activity, e.g., epileptiform activity. Thus the location and distribution of the inputs onto pyramidal cells are important parameters that influence neuronal activity in epilepsy. However, the location and distribution of inhibitory synapses converging onto pyramidal cells have not been fully studied. The objectives of this study are to investigate the roles of the relative location of inhibitory synapses on the dendritic tree and soma in the generation of bursting activity. We investigate influences of somatic and dendritic inhibition on bursting activity patterns in several paradigms of potential connections using a simplified multicompartmental model. We also investigate the effects of distribution of fast and slow components of GABAergic inhibition in pyramidal cells. Interspike interval (ISI) analysis is used for examination of bursting patterns. Simulations show that the inhibitory interneuron regulates neuronal bursting activity. Bursting behavior patterns depend on the synaptic weight and delay of the inhibitory connection as well as the location of the synapse. When the inhibitory interneuron synapses on the pyramidal neuron, inhibitory action is stronger if the inhibitory synapse is close to the soma. Alterations of synaptic weight of the interneuron can be compensatory for changes in the location of synaptic input. The relative changes in these parameters exert a considerable influence on whether synchronous bursting activity is facilitated or reduced. Additional simulations show that the slow GABAergic inhibitory component is more effective than the fast component in distal dendrites. Taken together, these findings illustrate the potential for GABAergic inhibition in the soma and dendritic tree to play an important modulatory role in bursting activity patterns.     

SALM synaptic cell adhesion-like molecules regulate the differentiation of excitatory synapses

Synaptic cell adhesion molecules (CAMs) are known to play key roles in various aspects of synaptic structures and functions, including early differentiation, maintenance, and plasticity. We herein report the identification of a family of cell adhesion-like molecules termed SALM that interacts with the abundant postsynaptic density (PSD) protein PSD-95. SALM2, a SALM isoform, distributes to excitatory, but not inhibitory, synaptic sites. Overexpression of SALM2 increases the number of excitatory synapses and dendritic spines. Mislocalized expression of SALM2 disrupts excitatory synapses and dendritic spines. Bead-induced direct aggregation of SALM2 results in coclustering of PSD-95 and other postsynaptic proteins, including GKAP and AMPA receptors. Knockdown of SALM2 by RNA interference reduces the number of excitatory synapses and dendritic spines and the frequency, but not amplitude, of miniature excitatory postsynaptic currents. These results suggest that SALM2 is an important regulator of the differentiation of excitatory synapses.