Strength Of Synaptic Inputs Research Articles

Synaptic alterations in pyramidal cells following genetic manipulation of neuronal excitability in monkey prefrontal cortex.

In schizophrenia, dorsolateral prefrontal cortex (DLPFC) pyramidal neurons (PNs) have both transcriptional and structural alterations that suggest they are hypoactive. PN hypoactivity is thought to produce synaptic alterations in schizophrenia, however the effects of lower neuronal activity on synaptic function in primate DLPFC have not been examined. Here, we used, for the first time in primate neocortex, adeno-associated viral vectors (AAVs) to reduce PN excitability with Kir2.1 channel overexpression and tested if this manipulation altered the strength of synaptic inputs onto the Kir2.1-overexpressing PNs. Recordings in DLPFC slices showed that Kir2.1 overexpression depressed excitatory (but not inhibitory), synaptic currents, suggesting that, in schizophrenia, the hypoactivity of PNs might be exacerbated by reduced strength of the excitatory synapses they receive.

Inhibiting presynaptic calcium channel motility in the auditory cortex suppresses synchronized input processing.

The emergent coherent population activity from thousands of stochastic neurons in the brain is believed to constitute a key neuronal mechanism for salient processing of external stimuli and its link to internal states like attention and perception. In the sensory cortex, functional cell assemblies are formed by recurrent excitation and inhibitory influences. The stochastic dynamics of each cell involved is largely orchestrated by presynaptic CAV2.1 voltage-gated calcium channels (VGCCs). Cav2.1 VGCCs initiate the release of neurotransmitters from the presynaptic compartment and are therefore able to add variability into synaptic transmission which can be partly explained by their mobile organization around docked vesicles. To investigate the relevance of Cav2.1 channel surface motility for the input processing in the primary auditory cortex (A1) in vivo, we make use of a new optogenetic system which allows for acute, reversable cross-linking Cav2.1 VGCCs via a photo-cross-linkable cryptochrome mutant, CRY2olig. In order to map neuronal activity across all cortical layers of the A1, we performed laminar current-source density (CSD) recordings with varying auditory stimulus sets in transgenic mice with a citrine tag on the N-terminus of the VGCCs. Clustering VGCCs suppresses overall sensory-evoked population activity, particularly when stimuli lead to a highly synchronized distribution of synaptic inputs. Our findings reveal the importance of membrane dynamics of presynaptic calcium channels for sensory encoding by dynamically adjusting network activity across a wide range of synaptic input strength.

Interactions between circuit architecture and plasticity in a closed-loop cerebellar system.

Determining the sites and directions of plasticity underlying changes in neural activity and behavior is critical for understanding mechanisms of learning. Identifying such plasticity from neural recording data can be challenging due to feedback pathways that impede reasoning about cause and effect. We studied interactions between feedback, neural activity, and plasticity in the context of a closed-loop motor learning task for which there is disagreement about the loci and directions of plasticity: vestibulo-ocular reflex learning. We constructed a set of circuit models that differed in the strength of their recurrent feedback, from no feedback to very strong feedback. Despite these differences, each model successfully fit a large set of neural and behavioral data. However, the patterns of plasticity predicted by the models fundamentally differed, with the direction of plasticity at a key site changing from depression to potentiation as feedback strength increased. Guided by our analysis, we suggest how such models can be experimentally disambiguated. Our results address a long-standing debate regarding cerebellum-dependent motor learning, suggesting a reconciliation in which learning-related changes in the strength of synaptic inputs to Purkinje cells are compatible with seemingly oppositely directed changes in Purkinje cell spiking activity. More broadly, these results demonstrate how changes in neural activity over learning can appear to contradict the sign of the underlying plasticity when either internal feedback or feedback through the environment is present.

In Vivo Optical Interrogation of Neuronal Responses to Genetic, Cell Type-Specific Silencing.

We established a low background, Cre-dependent version of the inducible Tet-On system for fast, cell type-specific transgene expression in vivo Coexpression of a constitutive, Cre-dependent fluorescent marker selectively allowed single-cell analyses before and after inducible, Tet-dependent transgene expression. Here, we used this method for precise, acute manipulation of neuronal activity in the living brain. The goal was to study neuronal network homeostasis at cellular resolution. Single induction of the potassium channel Kir2.1 produced cell type-specific silencing within hours that lasted for at least 3 d. Longitudinal in vivo imaging of spontaneous calcium transients and neuronal morphology demonstrated that prolonged silencing did not alter spine densities or synaptic input strength. Furthermore, selective induction of Kir2.1 in parvalbumin interneurons increased the activity of surrounding neurons in a distance-dependent manner. This high-resolution, inducible interference and interval imaging of individual cells (high I5, HighFive) method thus allows visualizing temporally precise, genetic perturbations of defined cells.SIGNIFICANCE STATEMENT Gene function is studied by KO or overexpression of a specific gene followed by analyses of phenotypic changes. However, being able to predict and analyze exactly those cells in which genetic manipulation will occur is not possible. We combined two prominent transgene overexpression methods to fluorescently highlight the targeted cells appropriately before cell type-specific transgene induction. By inducing a potassium channel that decreases neuronal firing, we investigated how neuronal networks in the living mouse brain possibly compensate swift changes in cellular activities. Unlike in vitro, known compensatory homeostatic mechanisms, such as changes in synapses, were not observed in vivo Overall, we demonstrated with our method rapid genetic manipulation and analysis of neuronal activities as well as precision transgene expression.

The Tripod neuron: a minimal structural reduction of the dendritic tree.

Neuron models with explicit dendritic dynamics have shed light on mechanisms for coincidence detection, pathway selection and temporal filtering. However, it is still unclear which morphological and physiological features are required to capture these phenomena. In this work, we introduce the Tripod neuron model and propose a minimal structural reduction of the dendritic tree that is able to reproduce these computations. The Tripod is a three-compartment model consisting of two segregated passive dendrites and a somatic compartment modelled as an adaptive, exponential integrate-and-fire neuron. It incorporates dendritic geometry, membrane physiology and receptor dynamics as measured in human pyramidal cells. We characterize the response of the Tripod to glutamatergic and GABAergic inputs and identify parameters that support supra-linear integration, coincidence-detection and pathway-specific gating through shunting inhibition. Following NMDA spikes, the Tripod neuron generates plateau potentials whose duration depends on the dendritic length and the strength of synaptic input. When fitted with distal compartments, the Tripod encodes previous activity into a dendritic depolarized state. This dendritic memory allows the neuron to perform temporal binding, and we show that it solves transition and sequence detection tasks on which a single-compartment model fails. Thus, the Tripod can account for dendritic computations previously explained only with more detailed neuron models or neural networks. Due to its simplicity, the Tripod neuron can be used efficiently in simulations of larger corticalcircuits. KEY POINTS: We present a neuron model, called the Tripod, with two segregated dendritic branches that are connected to an axosomatic compartment. Each branch implements inhibitory GABAergic and excitatory glutamatergic synaptic transmission, including voltage-gated NMDA receptors. Dendrites are modelled on relevant geometric and physiological parameters measured in human pyramidal cells. The neuron reproduces classical dendritic computations, such as coincidence detection and pathway selection via shunting inhibition, that are beyond the scope of point-neuron models. Under some conditions, dendritic NMDA spikes cause plateau potentials, and we show that they provide a form of short-term memory which is useful for sequence recognition. The dendritic structure of the Tripod neuron is sufficiently simple to be integrated into efficient network simulations and studied in a broad functional context.

Tonic Endocannabinoid Levels Modulate Retinal Signaling.

The endocannabinoid (eCB) system is critically involved in the modulation of synaptic transmission in the central nervous system, playing an important role in the control of emotional responses, neurodevelopment and synaptic plasticity among other functions. The eCB system is also present in the retina, with studies indicating changes in function after application of cannabinoid receptor agonists, antagonists and in knockout models. Whether eCBs are tonically released in the retina and their physiological functions is, however, still unknown. We investigated the role of the eCB system in the modulation of response strength of retinal ganglion cells (RGCs) to light stimulation, their receptive field organization, contrast sensitivity and excitability properties by performing whole-cell patch-clamp recordings in mouse RGCs before and after bath application of URB597, an inhibitor of the enzyme that degrades the eCB anandamide. Our results show that URB597 application leads to a reduction in the strength of synaptic inputs onto RGCs but paradoxically increases RGC excitability. In addition, URB597 was shown to modulate receptive field organization and contrast sensitivity of RGCs. We conclude that tonically released eCBs modulate retinal signaling by acting on traditional cannabinoid receptors (CB1R/CB2R) as well as on non-cannabinoid receptor targets. Thus, a thorough understanding of the effects of drugs that alter the endogenous cannabinoid levels and of exogenous cannabinoids is necessary to fully comprehend the impact of their medical as well as recreational use on vision.

CaMKIV Signaling Is Not Essential for the Maintenance of Intrinsic or Synaptic Properties in Mouse Visual Cortex.

Pyramidal neurons in rodent visual cortex homeostatically maintain their firing rates in vivo within a target range. In young cultured rat cortical neurons, Ca2+/calmodulin-dependent kinase IV (CaMKIV) signaling jointly regulates excitatory synaptic strength and intrinsic excitability to allow neurons to maintain their target firing rate. However, the role of CaMKIV signaling in regulating synaptic strength and intrinsic excitability in vivo has not been tested. Here, we show that in pyramidal neurons in visual cortex of juvenile male and female mice, CaMKIV signaling is not essential for the maintenance of basal synaptic or intrinsic properties. Neither CaMKIV conditional knock-down nor viral expression of dominant negative CaMKIV (dnCaMKIV) in vivo disrupts the intrinsic excitability or synaptic input strength of pyramidal neurons in primary visual cortex (V1), and CaMKIV signaling is not required for the increase in intrinsic excitability seen following monocular deprivation (MD). Viral expression of constitutively active CaMKIV (caCaMKIV) in vivo causes a complex disruption of the neuronal input/output function but does not affect synaptic input strength. Taken together, these results demonstrate that although augmented in vivo CaMKIV signaling can alter neuronal excitability, either endogenous CaMKIV signaling is dispensable for maintenance of excitability, or impaired CaMKIV signaling is robustly compensated.

Geometry and the Organizational Principle of Spine Synapses along a Dendrite.

Precise information on synapse organization in a dendrite is crucial to understanding the mechanisms underlying voltage integration and the variability in the strength of synaptic inputs across dendrites of different complex morphologies. Here, we used focused ion beam/scanning electron microscope (FIB/SEM) to image the dendritic spines of mice in the hippocampal CA1 region, CA3 region, somatosensory cortex, striatum, and cerebellum (CB). Our results show that the spine geometry and dimensions differ across neuronal cell types. Despite this difference, dendritic spines were organized in an orchestrated manner such that the postsynaptic density (PSD) area per unit length of dendrite scaled positively with the dendritic diameter in CA1 proximal stratum radiatum (PSR), cortex, and CB. The ratio of the PSD area to neck length was kept relatively uniform across dendrites of different diameters in CA1 PSR. Computer simulation suggests that a similar level of synaptic strength across different dendrites in CA1 PSR enables the effective transfer of synaptic inputs from the dendrites toward soma. Excitatory postsynaptic potentials (EPSPs), evoked at single spines by glutamate uncaging and recorded at the soma, show that the neck length is more influential than head width in regulating the EPSP magnitude at the soma. Our study describes thorough morphologic features and the organizational principles of dendritic spines in different brain regions.

Structure-function relation of the developing calyx of Held synapse in vivo.

Key points During development the giant, auditory calyx of Held forms a one‐to‐one connection with a principal neuron of the medial nucleus of the trapezoid body.While anatomical studies described that most of the target cells are temporarily contacted by multiple calyces, multi‐calyceal innervation was only sporadically observed in in vivo recordings, suggesting a structure–function discrepancy.We correlated synaptic strength of inputs, identified in in vivo recordings, with post hoc labelling of the recorded neuron and synaptic terminals containing vesicular glutamate transporters (VGluT).During development only one input increased to the level of the calyx of Held synapse, and its strength correlated with the large VGluT cluster contacting the postsynaptic soma.As neither competing strong inputs nor multiple large VGluT clusters on a single cell were observed, our findings did not indicate a structure–function discrepancy. In adult rodents, a principal neuron in the medial nucleus of the trapezoid (MNTB) is generally contacted by a single, giant axosomatic terminal called the calyx of Held. How this one‐on‐one relation is established is still unknown, but anatomical evidence suggests that during development principal neurons are innervated by multiple calyces, which may indicate calyceal competition. However, in vivo electrophysiological recordings from principal neurons indicated that only a single strong synaptic connection forms per cell. To test whether a mismatch exists between synaptic strength and terminal size, we compared the strength of synaptic inputs with the morphology of the synaptic terminals. In vivo whole‐cell recordings of the MNTB neurons from newborn Wistar rats of either sex were made while stimulating their afferent axons, allowing us to identify multiple inputs. The strength of the strongest input increased to calyceal levels in a few days across cells, while the strength of the second strongest input was stable. The recorded cells were subsequently immunolabelled for vesicular glutamate transporters (VGluT) to reveal axosomatic terminals with structured‐illumination microscopy. Synaptic strength of the strongest input was correlated with the contact area of the largest VGluT cluster at the soma (r = 0.8), and no indication of a mismatch between structure and strength was observed. Together, our data agree with a developmental scheme in which one input strengthens and becomes the calyx of Held, but not with multi‐calyceal competition.

Neurotrophic factors in the posterodorsal medial amygdala of male and cycling female rats

The posterodorsal medial amygdala (MePD) has a high concentration of receptors for gonadal hormones, is a sexually dimorphic region and dynamically controls the reproductive behavior of both males and females. Neurotrophic factors can promote dendritic spine remodeling and change synaptic input strength in a region-specific manner. Here, we analyzed the gene and protein expression of brain-derived neurotrophic factor (BDNF), insulin-like growth factor-I (IGF-1), polysialylated neural cell adhesion molecule (PSA-NCAM) and Ephrin-A4 in the MePD of adult males and females in diestrus, proestrus and estrus using real-time qPCR and fluorescent immunohistochemistry. The first approach showed their amplification except for Igf1 and the latter revealed that BDNF, IGF-1, PSA-NCAM and Ephrin-A4 are expressed in the MePD of the adult rats. Protein expression of these neurotrophic factors showed no differences between groups. However, proestrus females displayed a higher number of labelled puncta than males for BDNF expression and diestrus females for IGF-1 expression. In conjunction, results indicate that IGF-1 might be released rather than synthetized in the MePD, and the expression of specific neurotrophic factors varies specifically during proestrus. The dynamic modulation of BDNF and IGF-1 during this cyclic phase is coincident with synaptic changes and spine density remodeling in the MePD, the disinhibition of gonadotrophin secretion for ovulation and the display of sexual behavior.

Dopamine induces release of calcium from internal stores in layer II lateral entorhinal cortex fan cells.

The entorhinal cortex plays an important role in temporal lobe processes including learning and memory, object recognition, and contextual information processing. The alteration of the strength of synaptic inputs to the lateral entorhinal cortex may therefore contribute substantially to sensory and mnemonic functions. The neuromodulatory transmitter dopamine exerts powerful effects on excitatory glutamatergic synaptic transmission in the entorhinal cortex. Interestingly, inputs from midbrain dopamine neurons appear to specifically target clusters of excitatory cells located in the superficial layers of the entorhinal cortex. We have previously demonstrated that dopamine facilitates synaptic transmission through the activation of D1-like receptors. This facilitation of synaptic transmission is dependent on both activation of classical D1-like-receptors, and upon activation of dopamine receptors linked to increases in phospholipase C, inositol triphosphate (IP3), and intracellular calcium. In the present study we combined electrophysiological recordings of evoked excitatory postsynaptic currents with imaging of intracellular calcium using the fluorescent indicator fluo-4 to monitor calcium transients evoked by dopamine in electrophysiologically identified putative fan and pyramidal cells of the lateral entorhinal cortex. Bath application of dopamine (1 μM), or the phosphatidylinositol (PI)-linked D1-like-receptor agonist SKF83959 (5 μM), induced reliable and reversible increases in fluo-4 fluorescence and excitatory postsynaptic currents in fan cells, but not in pyramidal cells. In contrast, application of the classical D1-like-receptor agonist SKF38393 (10 μM) did not result in significant increases in fluorescence. Blocking release of calcium from internal stores by loading cells with the IP3 receptor blocker heparin (1 mM) or the ryanodine receptor blocker dantrolene (20 μM) abolished both the calcium transients and the facilitation of evoked synaptic currents induced by dopamine. Dopamine also induced calcium transients in fan cells when calcium was excluded from the extracellular medium, further indicating that the calcium transients are linked to release from internal stores. These results indicate that following D1-like-receptor binding, dopamine selectively induces transient elevations in intracellular calcium via activation of IP3 and ryanodine receptors, and that these elevations are linked to the facilitation of synaptic responses in putative layer II entorhinal cortex fan cells.

A Laminar Organization for Selective Cortico-Cortical Communication.

The neocortex is central to mammalian cognitive ability, playing critical roles in sensory perception, motor skills and executive function. This thin, layered structure comprises distinct, functionally specialized areas that communicate with each other through the axons of pyramidal neurons. For the hundreds of such cortico-cortical pathways to underlie diverse functions, their cellular and synaptic architectures must differ so that they result in distinct computations at the target projection neurons. In what ways do these pathways differ? By originating and terminating in different laminae, and by selectively targeting specific populations of excitatory and inhibitory neurons, these “interareal” pathways can differentially control the timing and strength of synaptic inputs onto individual neurons, resulting in layer-specific computations. Due to the rapid development in transgenic techniques, the mouse has emerged as a powerful mammalian model for understanding the rules by which cortical circuits organize and function. Here we review our understanding of how cortical lamination constrains long-range communication in the mammalian brain, with an emphasis on the mouse visual cortical network. We discuss the laminar architecture underlying interareal communication, the role of neocortical layers in organizing the balance of excitatory and inhibitory actions, and highlight the structure and function of layer 1 in mouse visual cortex.

Enhanced Excitatory Connectivity and Disturbed Sound Processing in the Auditory Brainstem of Fragile X Mice.

Hypersensitivity to sounds is one of the prevalent symptoms in individuals with Fragile X syndrome (FXS). It manifests behaviorally early during development and is often used as a landmark for treatment efficacy. However, the physiological mechanisms and circuit-level alterations underlying this aberrant behavior remain poorly understood. Using the mouse model of FXS (Fmr1 KO), we demonstrate that functional maturation of auditory brainstem synapses is impaired in FXS. Fmr1 KO mice showed a greatly enhanced excitatory synaptic input strength in neurons of the lateral superior olive (LSO), a prominent auditory brainstem nucleus, which integrates ipsilateral excitation and contralateral inhibition to compute interaural level differences. Conversely, the glycinergic, inhibitory input properties remained unaffected. The enhanced excitation was the result of an increased number of cochlear nucleus fibers converging onto one LSO neuron, without changing individual synapse properties. Concomitantly, immunolabeling of excitatory ending markers revealed an increase in the immunolabeled area, supporting abnormally elevated excitatory input numbers. Intrinsic firing properties were only slightly enhanced. In line with the disturbed development of LSO circuitry, auditory processing was also affected in adult Fmr1 KO mice as shown with single-unit recordings of LSO neurons. These processing deficits manifested as an increase in firing rate, a broadening of the frequency response area, and a shift in the interaural level difference function of LSO neurons. Our results suggest that this aberrant synaptic development of auditory brainstem circuits might be a major underlying cause of the auditory processing deficits in FXS.SIGNIFICANCE STATEMENT Fragile X Syndrome (FXS) is the most common inheritable form of intellectual impairment, including autism. A core symptom of FXS is extreme sensitivity to loud sounds. This is one reason why individuals with FXS tend to avoid social interactions, contributing to their isolation. Here, a mouse model of FXS was used to investigate the auditory brainstem where basic sound information is first processed. Loss of the Fragile X mental retardation protein leads to excessive excitatory compared with inhibitory inputs in neurons extracting information about sound levels. Functionally, this elevated excitation results in increased firing rates, and abnormal coding of frequency and binaural sound localization cues. Imbalanced early-stage sound level processing could partially explain the auditory processing deficits in FXS.

Decorrelated Input Dissociates Narrow Band γ Power and BOLD in Human Visual Cortex.

Although fMRI using the BOLD contrast is widely used for noninvasively mapping hemodynamic brain activity in humans, its exact link to underlying neural processing is poorly understood. Whereas some studies have reported that BOLD signals measured in visual cortex are tightly linked to neural activity in the narrow band γ (NBG) range, others have found a weak correlation between the two. To elucidate the mechanisms behind these conflicting findings, we hypothesized that BOLD reflects the strength of synaptic inputs to cortex, whereas NBG is more dependent on how well these inputs are correlated. To test this, we measured NBG, BOLD, and cerebral blood flow responses to stimuli that either correlate or decorrelate neural activity in human visual cortex. Next, we simulated a recurrent network model of excitatory and inhibitory neurons that reproduced in detail the experimental NBG and BOLD data. Results show that the visually evoked BOLD response was solely predicted by the sum of local inputs, whereas NBG was critically dependent on how well these inputs were correlated. In summary, the NBG-BOLD relationship strongly depends on the nature of sensory input to cortex: stimuli that increase the number of correlated inputs to visual cortex will increase NBG and BOLD in a similar manner, whereas stimuli that increase the number of decorrelated inputs will dissociate the two. The NBG-BOLD relationship is therefore not fixed but is rather highly dependent on input correlations that are both stimulus- and state-dependent.SIGNIFICANCE STATEMENT It is widely believed that γ oscillations in cortex are tightly linked to local hemodynamic activity. Here, we present experimental evidence showing how a stimulus can increase local blood flow to the brain despite suppressing γ power. Moreover, using a sophisticated model of cortical neurons, it is proposed that this occurs when synaptic input to cortex is strong yet decorrelated. Because input correlations are largely determined by the state of the brain, our results demonstrate that the relationship between γ and local hemodynamics is not fixed, but rather context dependent. This likely explains why certain neurodevelopmental disorders are characterized by weak γ activity despite showing normal blood flow.

High Pressure and [Ca 2+ ] Produce an Inverse Modulation of Synaptic Input Strength and Network Excitability in the Rat Dentate Gyrus.

Hyperbaric environments induce the high pressure neurological syndrome (HPNS) characterized by hyperexcitability of the central nervous system (CNS) and memory impairment. Human divers and other animals experience the HPNS at pressures beyond 1.1 MPa. High pressure depresses synaptic transmission and alters its dynamics in various animal models. Medial perforant path (MPP) synapses connecting the medial entorhinal cortex with the hippocampal formation are suppressed by 50% at 10.1MPa. Reduction of synaptic inputs is paradoxically associated with enhanced ability of dentate gyrus (DG)’ granule cells (GCs) to generate spikes at high pressure. This mechanism allows MPP inputs to elicit standard GC outputs at 0.1–25 Hz frequencies under hyperbaric conditions. An increased postsynaptic gain of MPP inputs probably allows diving animals to perform in hyperbaric environments, but makes them vulnerable to high intensity/frequency stimuli producing hyperexcitability. Increasing extracellular Ca2+ ([Ca2+]o) partially reverted pressure-mediated depression of MPP inputs and increased MPP’s low-pass filter properties. We postulated that raising [Ca2+]o in addition to increase synaptic inputs may reduce network excitability in the DG potentially improving its function and reducing sensitivity to high intensity and pathologic stimuli. For this matter, we activated the MPP with single and 50 Hz frequency stimuli that simulated physiologic and deleterious conditions, while assessing the GC’s output under various conditions of pressure and [Ca2+]o. Our results reveal that the pressure and [Ca2+]o produce an inverse modulation on synaptic input strength and network excitability. These coincident phenomena suggest a potential general mechanism of networks that adjusts gain as an inverse function of synaptic inputs’ strength. Such mechanism may serve for adaptation to variable pressure and other physiological and pathological conditions and may explain the increased sensitivity to strong sensory stimulation suffered by human deep-divers and cetaceans under hyperbaric conditions.

Recruitment of inhibition and excitation across mouse visual cortex depends on the hierarchy of interconnecting areas.

Diverse features of sensory stimuli are selectively processed in distinct brain areas. The relative recruitment of inhibitory and excitatory neurons within an area controls the gain of neurons for appropriate stimulus coding. We examined how such a balance of inhibition and excitation is differentially recruited across multiple levels of a cortical hierarchy by mapping the locations and strengths of synaptic inputs to pyramidal and parvalbumin (PV)-expressing neurons in feedforward and feedback pathways interconnecting primary (V1) and two higher visual areas. While interareal excitation was stronger in PV than in pyramidal neurons in all layer 2/3 pathways, we observed a gradual scaling down of the inhibition/excitation ratio from the most feedforward to the most feedback pathway. Our results indicate that interareal gain control depends on the hierarchical position of the source and the target, the direction of information flow through the network, and the laminar location of target neurons.

Spontaneous Release Regulates Synaptic Scaling in the Embryonic Spinal Network In Vivo.

Homeostatic plasticity mechanisms maintain cellular or network spiking activity within a physiologically functional range through compensatory changes in synaptic strength or intrinsic cellular excitability. Synaptic scaling is one form of homeostatic plasticity that is triggered after blockade of spiking or neurotransmission in which the strengths of all synaptic inputs to a cell are multiplicatively scaled upward or downward in a compensatory fashion. We have shown previously that synaptic upscaling could be triggered in chick embryo spinal motoneurons by complete blockade of spiking or GABAA receptor (GABAAR) activation for 2 d in vivo Here, we alter GABAAR activation in a more physiologically relevant manner by chronically adjusting presynaptic GABA release in vivo using nicotinic modulators or an mGluR2 agonist. Manipulating GABAAR activation in this way triggered scaling in a mechanistically similar manner to scaling induced by complete blockade of GABAARs. Remarkably, we find that altering action-potential (AP)-independent spontaneous release was able to fully account for the observed bidirectional scaling, whereas dramatic changes in spiking activity associated with spontaneous network activity had little effect on quantal amplitude. The reliance of scaling on an AP-independent process challenges the plasticity's relatedness to spiking in the living embryonic spinal network. Our findings have implications for the trigger and function of synaptic scaling and suggest that spontaneous release functions to regulate synaptic strength homeostatically in vivo Homeostatic synaptic scaling is thought to prevent inappropriate levels of spiking activity through compensatory adjustments in the strength of synaptic inputs. Therefore, it is thought that perturbations in spike rate trigger scaling. Here, we find that dramatic changes in spiking activity in the embryonic spinal cord have little effect on synaptic scaling; conversely, alterations in GABAA receptor activation due to action-potential-independent GABA vesicle release can trigger scaling. The findings suggest that scaling in the living embryonic spinal cord functions to maintain synaptic strength and challenge the view that scaling acts to regulate spiking activity homeostatically. Finally, the results indicate that fetal exposure to drugs that influence GABA spontaneous release, such as nicotine, could profoundly affect synaptic maturation.

Pathway-Specific Remodeling of Thalamostriatal Synapses in Parkinsonian Mice

Movement suppression in Parkinson's disease (PD) is thought to arise from increased efficacy of the indirect pathway basal ganglia circuit, relative to the direct pathway. However, the underlying pathophysiological mechanisms remain elusive. To examine whether changes in the strength of synaptic inputs to these circuits contribute to this imbalance, we obtained paired whole-cell recordings from striatal direct- and indirect-pathway medium spiny neurons (dMSNs and iMSNs) and optically stimulated inputs from sensorimotor cortex or intralaminar thalamus in brain slices from control and dopamine-depleted mice. We found that dopamine depletion selectively decreased synaptic strength at thalamic inputs to dMSNs, suggesting that thalamus drives asymmetric activation of basal ganglia circuitry underlying parkinsonian motor impairments. Consistent with this hypothesis, in vivo chemogenetic and optogenetic inhibition of thalamostriatal terminals reversed motor deficits in dopamine-depleted mice. These results implicate thalamostriatal projections in the pathophysiology of PD and support interventions targeting thalamus as a potential therapeutic strategy.

Reconciling homeostatic and use-dependent plasticity in the context of somatosensory deprivation.

The concept of homeostatic plasticity postulates that neurons maintain relatively stable rates of firing despite changing inputs. Homeostatic and use-dependent plasticity mechanisms operate concurrently, although they have different requirements for induction. Depriving central somatosensory neurons of their primary activating inputs reduces activity and results in compensatory changes that favor excitation. Both a reduction of GABAergic inhibition and increase in glutamatergic excitatory transmission are observed in input-deprived cortex. Topographic reorganization of the adult somatosensory cortex is likely driven by both homeostatic and use-dependent mechanisms. Plasticity is induced by changes in the strengths of synaptic inputs, as well as changes in temporal correlation of neuronal activity. However, there is less certainty regarding the in vivo contribution of homeostatic mechanisms as in vitro experiments rely on manipulations that create states that do not normally occur in the living nervous system. Homeostatic plasticity seems to occur, but more in vivo research is needed to determine mechanisms. In vitro research is also needed but should better conform to conditions that might occur naturally in vivo.

Cellular mechanisms for response heterogeneity among L2/3 pyramidal cells in whisker somatosensory cortex.

Whisker deflection evokes sparse, low-probability spiking among L2/3 pyramidal cells in rodent somatosensory cortex (S1), with spiking distributed nonuniformly between more and less responsive cells. The cellular and local circuit factors that determine whisker responsiveness across neurons are unclear. To identify these factors, we used two-photon calcium imaging and loose-seal recording to identify more and less responsive L2/3 neurons in S1 slices in vitro, during feedforward recruitment of the L2/3 network by L4 stimulation. We observed a broad gradient of spike recruitment thresholds within local L2/3 populations, with low- and high-threshold cells intermixed. This recruitment gradient was significantly correlated across different L4 stimulation sites, and between L4-evoked and whisker-evoked responses in vivo, indicating that a substantial component of responsiveness is independent of tuning to specific feedforward inputs. Low- and high-threshold L2/3 pyramidal cells differed in L4-evoked excitatory synaptic conductance and intrinsic excitability, including spike threshold and the likelihood of doublet spike bursts. A gradient of intrinsic excitability was observed across neurons. Cells that spiked most readily to L4 stimulation received the most synaptic excitation but had the lowest intrinsic excitability. Low- and high-threshold cells did not differ in dendritic morphology, passive membrane properties, or L4-evoked inhibitory conductance. Thus multiple gradients of physiological properties exist across L2/3 pyramidal cells, with excitatory synaptic input strength best predicting overall spiking responsiveness during network recruitment.