Browsing by Subject "Synapses"

Now showing 1 - 20 of 25

Open Access
A cerebellar learning model of vestibulo-ocular reflex adaptation in wild-type and mutant mice.
(The Journal of neuroscience : the official journal of the Society for Neuroscience, 2014-05) Clopath, Claudia; Badura, Aleksandra; De Zeeuw, Chris I; Brunel, Nicolas
Mechanisms of cerebellar motor learning are still poorly understood. The standard Marr-Albus-Ito theory posits that learning involves plasticity at the parallel fiber to Purkinje cell synapses under control of the climbing fiber input, which provides an error signal as in classical supervised learning paradigms. However, a growing body of evidence challenges this theory, in that additional sites of plasticity appear to contribute to motor adaptation. Here, we consider phase-reversal training of the vestibulo-ocular reflex (VOR), a simple form of motor learning for which a large body of experimental data is available in wild-type and mutant mice, in which the excitability of granule cells or inhibition of Purkinje cells was affected in a cell-specific fashion. We present novel electrophysiological recordings of Purkinje cell activity measured in naive wild-type mice subjected to this VOR adaptation task. We then introduce a minimal model that consists of learning at the parallel fibers to Purkinje cells with the help of the climbing fibers. Although the minimal model reproduces the behavior of the wild-type animals and is analytically tractable, it fails at reproducing the behavior of mutant mice and the electrophysiology data. Therefore, we build a detailed model involving plasticity at the parallel fibers to Purkinje cells' synapse guided by climbing fibers, feedforward inhibition of Purkinje cells, and plasticity at the mossy fiber to vestibular nuclei neuron synapse. The detailed model reproduces both the behavioral and electrophysiological data of both the wild-type and mutant mice and allows for experimentally testable predictions.
Open Access
A craniofacial-specific monosynaptic circuit enables heightened affective pain.
(Nature neuroscience, 2017-12) Rodriguez, Erica; Sakurai, Katsuyasu; Xu, Jennie; Chen, Yong; Toda, Koji; Zhao, Shengli; Han, Bao-Xia; Ryu, David; Yin, Henry; Liedtke, Wolfgang; Wang, Fan
Humans often rank craniofacial pain as more severe than body pain. Evidence suggests that a stimulus of the same intensity induces stronger pain in the face than in the body. However, the underlying neural circuitry for the differential processing of facial versus bodily pain remains unknown. Interestingly, the lateral parabrachial nucleus (PBL), a critical node in the affective pain circuit, is activated more strongly by noxious stimulation of the face than of the hindpaw. Using a novel activity-dependent technology called CANE developed in our laboratory, we identified and selectively labeled noxious-stimulus-activated PBL neurons and performed comprehensive anatomical input-output mapping. Surprisingly, we uncovered a hitherto uncharacterized monosynaptic connection between cranial sensory neurons and the PBL-nociceptive neurons. Optogenetic activation of this monosynaptic craniofacial-to-PBL projection induced robust escape and avoidance behaviors and stress calls, whereas optogenetic silencing specifically reduced facial nociception. The monosynaptic circuit revealed here provides a neural substrate for heightened craniofacial affective pain.
Open Access
Activation of Rod Input in a Model of Retinal Degeneration Reverses Retinal Remodeling and Induces Formation of Functional Synapses and Recovery of Visual Signaling in the Adult Retina.
(The Journal of neuroscience : the official journal of the Society for Neuroscience, 2019-08) Wang, Tian; Pahlberg, Johan; Cafaro, Jon; Frederiksen, Rikard; Cooper, AJ; Sampath, Alapakkam P; Field, Greg D; Chen, Jeannie
A major cause of human blindness is the death of rod photoreceptors. As rods degenerate, synaptic structures between rod and rod bipolar cells disappear and the rod bipolar cells extend their dendrites and occasionally make aberrant contacts. Such changes are broadly observed in blinding disorders caused by photoreceptor cell death and are thought to occur in response to deafferentation. How the remodeled retinal circuit affects visual processing following rod rescue is not known. To address this question, we generated male and female transgenic mice wherein a disrupted cGMP-gated channel (CNG) gene can be repaired at the endogenous locus and at different stages of degeneration by tamoxifen-inducible cre-mediated recombination. In normal rods, light-induced closure of CNG channels leads to hyperpolarization of the cell, reducing neurotransmitter release at the synapse. Similarly, rods lacking CNG channels exhibit a resting membrane potential that was ~10 mV hyperpolarized compared to WT rods, indicating diminished glutamate release. Retinas from these mice undergo stereotypic retinal remodeling as a consequence of rod malfunction and degeneration. Upon tamoxifen-induced expression of CNG channels, rods recovered their structure and exhibited normal light responses. Moreover, we show that the adult mouse retina displays a surprising degree of plasticity upon activation of rod input. Wayward bipolar cell dendrites establish contact with rods to support normal synaptic transmission, which is propagated to the retinal ganglion cells. These findings demonstrate remarkable plasticity extending beyond the developmental period and support efforts to repair or replace defective rods in patients blinded by rod degeneration.SIGNIFICANCE STATEMENT Current strategies for treatment of neurodegenerative disorders are focused on the repair of the primary affected cell type. However, the defective neurons function within a complex neural circuitry, which also becomes degraded during disease. It is not known whether rescued neurons and the remodeled circuit will establish communication to regain normal function. We show that the adult mammalian neural retina exhibits a surprising degree of plasticity following rescue of rod photoreceptors. The wayward dendrites of rod bipolar cells re-establish contact with rods to support normal synaptic transmission, which is propagated to the retinal ganglion cells. These findings support efforts to repair or replace defective rods in patients blinded by rod cell loss.
Open Access
Astrocytes refine cortical connectivity at dendritic spines.
(Elife, 2014-12-17) Risher, WC; Patel, S; Kim, IH; Uezu, A; Bhagat, S; Wilton, DK; Pilaz, L; Singh Alvarado, J; Calhan, OY; Silver, DL; Stevens, B; Calakos, N; Soderling, SH; Eroglu, C
During cortical synaptic development, thalamic axons must establish synaptic connections despite the presence of the more abundant intracortical projections. How thalamocortical synapses are formed and maintained in this competitive environment is unknown. Here, we show that astrocyte-secreted protein hevin is required for normal thalamocortical synaptic connectivity in the mouse cortex. Absence of hevin results in a profound, long-lasting reduction in thalamocortical synapses accompanied by a transient increase in intracortical excitatory connections. Three-dimensional reconstructions of cortical neurons from serial section electron microscopy (ssEM) revealed that, during early postnatal development, dendritic spines often receive multiple excitatory inputs. Immuno-EM and confocal analyses revealed that majority of the spines with multiple excitatory contacts (SMECs) receive simultaneous thalamic and cortical inputs. Proportion of SMECs diminishes as the brain develops, but SMECs remain abundant in Hevin-null mice. These findings reveal that, through secretion of hevin, astrocytes control an important developmental synaptic refinement process at dendritic spines.
Open Access
Astrocytes: Orchestrating synaptic plasticity?
(Neuroscience, 2016-05) De Pittà, M; Brunel, N; Volterra, A
Synaptic plasticity is the capacity of a preexisting connection between two neurons to change in strength as a function of neural activity. Because synaptic plasticity is the major candidate mechanism for learning and memory, the elucidation of its constituting mechanisms is of crucial importance in many aspects of normal and pathological brain function. In particular, a prominent aspect that remains debated is how the plasticity mechanisms, that encompass a broad spectrum of temporal and spatial scales, come to play together in a concerted fashion. Here we review and discuss evidence that pinpoints to a possible non-neuronal, glial candidate for such orchestration: the regulation of synaptic plasticity by astrocytes.
Open Access
Calcium-based plasticity model explains sensitivity of synaptic changes to spike pattern, rate, and dendritic location.
(Proceedings of the National Academy of Sciences of the United States of America, 2012-03) Graupner, Michael; Brunel, Nicolas
Multiple stimulation protocols have been found to be effective in changing synaptic efficacy by inducing long-term potentiation or depression. In many of those protocols, increases in postsynaptic calcium concentration have been shown to play a crucial role. However, it is still unclear whether and how the dynamics of the postsynaptic calcium alone determine the outcome of synaptic plasticity. Here, we propose a calcium-based model of a synapse in which potentiation and depression are activated above calcium thresholds. We show that this model gives rise to a large diversity of spike timing-dependent plasticity curves, most of which have been observed experimentally in different systems. It accounts quantitatively for plasticity outcomes evoked by protocols involving patterns with variable spike timing and firing rate in hippocampus and neocortex. Furthermore, it allows us to predict that differences in plasticity outcomes in different studies are due to differences in parameters defining the calcium dynamics. The model provides a mechanistic understanding of how various stimulation protocols provoke specific synaptic changes through the dynamics of calcium concentration and thresholds implementing in simplified fashion protein signaling cascades, leading to long-term potentiation and long-term depression. The combination of biophysical realism and analytical tractability makes it the ideal candidate to study plasticity at the synapse, neuron, and network levels.
Open Access
Chemogenetics-mediated acute inhibition of excitatory neuronal activity improves stroke outcome.
(Experimental neurology, 2020-04) Wang, Ya-Chao; Galeffi, Francesca; Wang, Wei; Li, Xuan; Lu, Liping; Sheng, Huaxin; Hoffmann, Ulrike; Turner, Dennis A; Yang, Wei
Background and purpose
Ischemic stroke significantly perturbs neuronal homeostasis leading to a cascade of pathologic events causing brain damage. In this study, we assessed acute stroke outcome after chemogenetic inhibition of forebrain excitatory neuronal activity.
Methods
We generated hM4Di-TG transgenic mice expressing the inhibitory hM4Di, a Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-based chemogenetic receptor, in forebrain excitatory neurons. Clozapine-N-oxide (CNO) was used to activate hM4Di DREADD. Ischemic stroke was induced by transient occlusion of the middle cerebral artery. Neurologic function and infarct volumes were evaluated. Excitatory neuronal suppression in the hM4Di-TG mouse forebrain was assessed electrophysiologically in vitro and in vivo, based on evoked synaptic responses, and in vivo based on occurrence of potassium-induced cortical spreading depolarizations.
Results
Detailed characterization of hM4Di-TG mice confirmed that evoked synaptic responses in both in vitro hippocampal slices and in vivo motor cortex were significantly reduced after CNO-mediated activation of the inhibitory hM4Di DREADD. Further, CNO treatment had no obvious effects on physiology and motor function in either control or hM4Di-TG mice. Importantly, hM4Di-TG mice treated with CNO at either 10 min before ischemia or 30 min after reperfusion exhibited significantly improved neurologic function and smaller infarct volumes compared to CNO-treated control mice. Mechanistically, we showed that potassium-induced cortical spreading depression episodes were inhibited, including frequency and duration of DC shift, in CNO-treated hM4Di-TG mice.
Conclusions
Our data demonstrate that acute inhibition of a subset of excitatory neurons after ischemic stroke can prevent brain injury and improve functional outcome. This study, together with the previous work in optogenetic neuronal modulation during the chronic phase of stroke, supports the notion that targeting neuronal activity is a promising strategy in stroke therapy.
Open Access
Estimating network parameters from combined dynamics of firing rate and irregularity of single neurons.
(Journal of neurophysiology, 2011-01) Hamaguchi, Kosuke; Riehle, Alexa; Brunel, Nicolas
High firing irregularity is a hallmark of cortical neurons in vivo, and modeling studies suggest a balance of excitation and inhibition is necessary to explain this high irregularity. Such a balance must be generated, at least partly, from local interconnected networks of excitatory and inhibitory neurons, but the details of the local network structure are largely unknown. The dynamics of the neural activity depends on the local network structure; this in turn suggests the possibility of estimating network structure from the dynamics of the firing statistics. Here we report a new method to estimate properties of the local cortical network from the instantaneous firing rate and irregularity (CV(2)) under the assumption that recorded neurons are a part of a randomly connected sparse network. The firing irregularity, measured in monkey motor cortex, exhibits two features; many neurons show relatively stable firing irregularity in time and across different task conditions; the time-averaged CV(2) is widely distributed from quasi-regular to irregular (CV(2) = 0.3-1.0). For each recorded neuron, we estimate the three parameters of a local network [balance of local excitation-inhibition, number of recurrent connections per neuron, and excitatory postsynaptic potential (EPSP) size] that best describe the dynamics of the measured firing rates and irregularities. Our analysis shows that optimal parameter sets form a two-dimensional manifold in the three-dimensional parameter space that is confined for most of the neurons to the inhibition-dominated region. High irregularity neurons tend to be more strongly connected to the local network, either in terms of larger EPSP and inhibitory PSP size or larger number of recurrent connections, compared with the low irregularity neurons, for a given excitatory/inhibitory balance. Incorporating either synaptic short-term depression or conductance-based synapses leads many low CV(2) neurons to move to the excitation-dominated region as well as to an increase of EPSP size.
Open Access
Frontal eye field neurons orthodromically activated from the superior colliculus.
(J Neurophysiol, 1998-12) Sommer, MA; Wurtz, RH
Frontal eye field neurons orthodromically activated from the superior colliculus. J. Neurophysiol. 80: 3331-3333, 1998. Anatomical studies have shown that the frontal eye field (FEF) and superior colliculus (SC) of monkeys are reciprocally connected, and a physiological study described the signals sent from the FEF to the SC. Nothing is known, however, about the signals sent from the SC to the FEF. We physiologically identified and characterized FEF neurons that are likely to receive input from the SC. Fifty-two FEF neurons were found that were orthodromically activated by electrical stimulation of the intermediate or deeper layers of the SC. All the neurons that we tested (n = 34) discharged in response to visual stimulation. One-half also discharged when saccadic eye movements were made. This provides the first direct evidence that the ascending pathway from SC to FEF might carry visual- and saccade-related signals. Our findings support a hypothesis that the SC and the FEF interact bidirectionally during the events leading up to saccade generation.
Open Access
Huntingtin is required for normal excitatory synapse development in cortical and striatal circuits.
(J Neurosci, 2014-07-09) McKinstry, Spencer U; Karadeniz, Yonca B; Worthington, Atesh K; Hayrapetyan, Volodya Y; Ozlu, M Ilcim; Serafin-Molina, Karol; Risher, W Christopher; Ustunkaya, Tuna; Dragatsis, Ioannis; Zeitlin, Scott; Yin, Henry H; Eroglu, Cagla
Huntington's disease (HD) is a neurodegenerative disease caused by the expansion of a poly-glutamine (poly-Q) stretch in the huntingtin (Htt) protein. Gain-of-function effects of mutant Htt have been extensively investigated as the major driver of neurodegeneration in HD. However, loss-of-function effects of poly-Q mutations recently emerged as potential drivers of disease pathophysiology. Early synaptic problems in the excitatory cortical and striatal connections have been reported in HD, but the role of Htt protein in synaptic connectivity was unknown. Therefore, we investigated the role of Htt in synaptic connectivity in vivo by conditionally silencing Htt in the developing mouse cortex. When cortical Htt function was silenced, cortical and striatal excitatory synapses formed and matured at an accelerated pace through postnatal day 21 (P21). This exuberant synaptic connectivity was lost over time in the cortex, resulting in the deterioration of synapses by 5 weeks. Synaptic decline in the cortex was accompanied with layer- and region-specific reactive gliosis without cell loss. To determine whether the disease-causing poly-Q mutation in Htt affects synapse development, we next investigated the synaptic connectivity in a full-length knock-in mouse model of HD, the zQ175 mouse. Similar to the cortical conditional knock-outs, we found excessive excitatory synapse formation and maturation in the cortices of P21 zQ175, which was lost by 5 weeks. Together, our findings reveal that cortical Htt is required for the correct establishment of cortical and striatal excitatory circuits, and this function of Htt is lost when the mutant Htt is present.
Open Access
Intracellular Neural Recording with Pure Carbon Nanotube Probes.
(PloS one, 2013-01) Yoon, Inho; Hamaguchi, Kosuke; Borzenets, Ivan V; Finkelstein, Gleb; Mooney, Richard; Donald, Bruce R
The computational complexity of the brain depends in part on a neuron's capacity to integrate electrochemical information from vast numbers of synaptic inputs. The measurements of synaptic activity that are crucial for mechanistic understanding of brain function are also challenging, because they require intracellular recording methods to detect and resolve millivolt- scale synaptic potentials. Although glass electrodes are widely used for intracellular recordings, novel electrodes with superior mechanical and electrical properties are desirable, because they could extend intracellular recording methods to challenging environments, including long term recordings in freely behaving animals. Carbon nanotubes (CNTs) can theoretically deliver this advance, but the difficulty of assembling CNTs has limited their application to a coating layer or assembly on a planar substrate, resulting in electrodes that are more suitable for in vivo extracellular recording or extracellular recording from isolated cells. Here we show that a novel, yet remarkably simple, millimeter-long electrode with a sub-micron tip, fabricated from self-entangled pure CNTs can be used to obtain intracellular and extracellular recordings from vertebrate neurons in vitro and in vivo. This fabrication technology provides a new method for assembling intracellular electrodes from CNTs, affording a promising opportunity to harness nanotechnology for neuroscience applications.
Open Access
Memory capacity of networks with stochastic binary synapses.
(PLoS Comput Biol, 2014-08) Dubreuil, Alexis M; Amit, Yali; Brunel, Nicolas
In standard attractor neural network models, specific patterns of activity are stored in the synaptic matrix, so that they become fixed point attractors of the network dynamics. The storage capacity of such networks has been quantified in two ways: the maximal number of patterns that can be stored, and the stored information measured in bits per synapse. In this paper, we compute both quantities in fully connected networks of N binary neurons with binary synapses, storing patterns with coding level [Formula: see text], in the large [Formula: see text] and sparse coding limits ([Formula: see text]). We also derive finite-size corrections that accurately reproduce the results of simulations in networks of tens of thousands of neurons. These methods are applied to three different scenarios: (1) the classic Willshaw model, (2) networks with stochastic learning in which patterns are shown only once (one shot learning), (3) networks with stochastic learning in which patterns are shown multiple times. The storage capacities are optimized over network parameters, which allows us to compare the performance of the different models. We show that finite-size effects strongly reduce the capacity, even for networks of realistic sizes. We discuss the implications of these results for memory storage in the hippocampus and cerebral cortex.
Open Access
Memory maintenance in synapses with calcium-based plasticity in the presence of background activity.
(PLoS Comput Biol, 2014-10) Higgins, David; Graupner, Michael; Brunel, Nicolas
Most models of learning and memory assume that memories are maintained in neuronal circuits by persistent synaptic modifications induced by specific patterns of pre- and postsynaptic activity. For this scenario to be viable, synaptic modifications must survive the ubiquitous ongoing activity present in neural circuits in vivo. In this paper, we investigate the time scales of memory maintenance in a calcium-based synaptic plasticity model that has been shown recently to be able to fit different experimental data-sets from hippocampal and neocortical preparations. We find that in the presence of background activity on the order of 1 Hz parameters that fit pyramidal layer 5 neocortical data lead to a very fast decay of synaptic efficacy, with time scales of minutes. We then identify two ways in which this memory time scale can be extended: (i) the extracellular calcium concentration in the experiments used to fit the model are larger than estimated concentrations in vivo. Lowering extracellular calcium concentration to in vivo levels leads to an increase in memory time scales of several orders of magnitude; (ii) adding a bistability mechanism so that each synapse has two stable states at sufficiently low background activity leads to a further boost in memory time scale, since memory decay is no longer described by an exponential decay from an initial state, but by an escape from a potential well. We argue that both features are expected to be present in synapses in vivo. These results are obtained first in a single synapse connecting two independent Poisson neurons, and then in simulations of a large network of excitatory and inhibitory integrate-and-fire neurons. Our results emphasise the need for studying plasticity at physiological extracellular calcium concentration, and highlight the role of synaptic bi- or multistability in the stability of learned synaptic structures.
Open Access
Mitochondrial ROS cause motor deficits induced by synaptic inactivity: Implications for synapse pruning.
(Redox biology, 2018-06) Sidlauskaite, Eva; Gibson, Jack W; Megson, Ian L; Whitfield, Philip D; Tovmasyan, Artak; Batinic-Haberle, Ines; Murphy, Michael P; Moult, Peter R; Cobley, James N
Developmental synapse pruning refines burgeoning connectomes. The basic mechanisms of mitochondrial reactive oxygen species (ROS) production suggest they select inactive synapses for pruning: whether they do so is unknown. To begin to unravel whether mitochondrial ROS regulate pruning, we made the local consequences of neuromuscular junction (NMJ) pruning detectable as motor deficits by using disparate exogenous and endogenous models to induce synaptic inactivity en masse in developing Xenopus laevis tadpoles. We resolved whether: (1) synaptic inactivity increases mitochondrial ROS; and (2) chemically heterogeneous antioxidants rescue synaptic inactivity induced motor deficits. Regardless of whether it was achieved with muscle (α-bungarotoxin), nerve (α-latrotoxin) targeted neurotoxins or an endogenous pruning cue (SPARC), synaptic inactivity increased mitochondrial ROS in vivo. The manganese porphyrins MnTE-2-PyP5+ and/or MnTnBuOE-2-PyP5+ blocked mitochondrial ROS to significantly reduce neurotoxin and endogenous pruning cue induced motor deficits. Selectively inducing mitochondrial ROS-using mitochondria-targeted Paraquat (MitoPQ)-recapitulated synaptic inactivity induced motor deficits; which were significantly reduced by blocking mitochondrial ROS with MnTnBuOE-2-PyP5+. We unveil mitochondrial ROS as synaptic activity sentinels that regulate the phenotypical consequences of forced synaptic inactivity at the NMJ. Our novel results are relevant to pruning because synaptic inactivity is one of its defining features.
Open Access
Modulation of Synaptic Plasticity by Glutamatergic Gliotransmission: A Modeling Study.
(Neural plasticity, 2016-01) De Pittà, Maurizio; Brunel, Nicolas
Glutamatergic gliotransmission, that is, the release of glutamate from perisynaptic astrocyte processes in an activity-dependent manner, has emerged as a potentially crucial signaling pathway for regulation of synaptic plasticity, yet its modes of expression and function in vivo remain unclear. Here, we focus on two experimentally well-identified gliotransmitter pathways, (i) modulations of synaptic release and (ii) postsynaptic slow inward currents mediated by glutamate released from astrocytes, and investigate their possible functional relevance on synaptic plasticity in a biophysical model of an astrocyte-regulated synapse. Our model predicts that both pathways could profoundly affect both short- and long-term plasticity. In particular, activity-dependent glutamate release from astrocytes could dramatically change spike-timing-dependent plasticity, turning potentiation into depression (and vice versa) for the same induction protocol.
Open Access
Novel hybrid action of GABA mediates inhibitory feedback in the mammalian retina.
(PLoS biology, 2019-04) Grove, James CR; Hirano, Arlene A; de Los Santos, Janira; McHugh, Cyrus F; Purohit, Shashvat; Field, Greg D; Brecha, Nicholas C; Barnes, Steven
The stream of visual information sent from photoreceptors to second-order bipolar cells is intercepted by laterally interacting horizontal cells that generate feedback to optimize and improve the efficiency of signal transmission. The mechanisms underlying the regulation of graded photoreceptor synaptic output in this nonspiking network have remained elusive. Here, we analyze with patch clamp recording the novel mechanisms by which horizontal cells control pH in the synaptic cleft to modulate photoreceptor neurotransmitter release. First, we show that mammalian horizontal cells respond to their own GABA release and that the results of this autaptic action affect cone voltage-gated Ca2+ channel (CaV channel) gating through changes in pH. As a proof-of-principle, we demonstrate that chemogenetic manipulation of horizontal cells with exogenous anion channel expression mimics GABA-mediated cone CaV channel inhibition. Activation of these GABA receptor anion channels can depolarize horizontal cells and increase cleft acidity via Na+/H+ exchanger (NHE) proton extrusion, which results in inhibition of cone CaV channels. This action is effectively counteracted when horizontal cells are sufficiently hyperpolarized by increased GABA receptor (GABAR)-mediated HCO3- efflux, alkalinizing the cleft and disinhibiting cone CaV channels. This demonstrates how hybrid actions of GABA operate in parallel to effect voltage-dependent pH changes, a novel mechanism for regulating synaptic output.
Open Access
Optimal properties of analog perceptrons with excitatory weights.
(PLoS Comput Biol, 2013) Clopath, Claudia; Brunel, Nicolas
The cerebellum is a brain structure which has been traditionally devoted to supervised learning. According to this theory, plasticity at the Parallel Fiber (PF) to Purkinje Cell (PC) synapses is guided by the Climbing fibers (CF), which encode an 'error signal'. Purkinje cells have thus been modeled as perceptrons, learning input/output binary associations. At maximal capacity, a perceptron with excitatory weights expresses a large fraction of zero-weight synapses, in agreement with experimental findings. However, numerous experiments indicate that the firing rate of Purkinje cells varies in an analog, not binary, manner. In this paper, we study the perceptron with analog inputs and outputs. We show that the optimal input has a sparse binary distribution, in good agreement with the burst firing of the Granule cells. In addition, we show that the weight distribution consists of a large fraction of silent synapses, as in previously studied binary perceptron models, and as seen experimentally.
Open Access
Paternal Δ9-Tetrahydrocannabinol Exposure Prior to Mating Elicits Deficits in Cholinergic Synaptic Function in the Offspring.
(Toxicological sciences : an official journal of the Society of Toxicology, 2020-04) Slotkin, Theodore A; Skavicus, Samantha; Levin, Edward D; Seidler, Frederic J
Little attention has been paid to the potential impact of paternal marijuana use on offspring brain development. We administered Δ9-tetrahydrocannabinol (THC, 0, 2, or 4 mg/kg/day) to male rats for 28 days. Two days after the last THC treatment, the males were mated to drug-naïve females. We then assessed the impact on development of acetylcholine (ACh) systems in the offspring, encompassing the period from the onset of adolescence (postnatal day 30) through middle age (postnatal day 150), and including brain regions encompassing the majority of ACh terminals and cell bodies. Δ9-Tetrahydrocannabinol produced a dose-dependent deficit in hemicholinium-3 binding, an index of presynaptic ACh activity, superimposed on regionally selective increases in choline acetyltransferase activity, a biomarker for numbers of ACh terminals. The combined effects produced a persistent decrement in the hemicholinium-3/choline acetyltransferase ratio, an index of impulse activity per nerve terminal. At the low THC dose, the decreased presynaptic activity was partially compensated by upregulation of nicotinic ACh receptors, whereas at the high dose, receptors were subnormal, an effect that would exacerbate the presynaptic defect. Superimposed on these effects, either dose of THC also accelerated the age-related decline in nicotinic ACh receptors. Our studies provide evidence for adverse effects of paternal THC administration on neurodevelopment in the offspring and further demonstrate that adverse impacts of drug exposure on brain development are not limited to effects mediated by the embryonic or fetal chemical environment, but rather that vulnerability is engendered by exposures occurring prior to conception, involving the father as well as the mother.
Open Access
Regulation of spine structural plasticity by Arc/Arg3.1.
(Seminars in cell & developmental biology, 2018-05) Newpher, Thomas M; Harris, Scott; Pringle, Jasmine; Hamilton, Colleen; Soderling, Scott
Dendritic spines are actin-rich, postsynaptic protrusions that contact presynaptic terminals to form excitatory chemical synapses. These synaptic contacts are widely believed to be the sites of memory formation and information storage, and changes in spine shape are thought to underlie several forms of learning-related plasticity. Both membrane trafficking pathways and the actin cytoskeleton drive activity-dependent structural and functional changes in dendritic spines. A key molecular player in regulating these processes is the activity-regulated cytoskeleton-associated protein (Arc), a protein that has diverse roles in expression of synaptic plasticity. In this review, we highlight important findings that have shaped our understanding of Arc's functions in structural and functional plasticity, as well as Arc's contributions to memory consolidation and disease.
Open Access
Sequential ionic and conformational signaling by calcium channels drives neuronal gene expression.
(Science, 2016-02-19) Li, Boxing; Tadross, Michael R; Tsien, Richard W
Voltage-gated CaV1.2 channels (L-type calcium channel α1C subunits) are critical mediators of transcription-dependent neural plasticity. Whether these channels signal via the influx of calcium ion (Ca(2+)), voltage-dependent conformational change (VΔC), or a combination of the two has thus far been equivocal. We fused CaV1.2 to a ligand-gated Ca(2+)-permeable channel, enabling independent control of localized Ca(2+) and VΔC signals. This revealed an unexpected dual requirement: Ca(2+) must first mobilize actin-bound Ca(2+)/calmodulin-dependent protein kinase II, freeing it for subsequent VΔC-mediated accumulation. Neither signal alone sufficed to activate transcription. Signal order was crucial: Efficiency peaked when Ca(2+) preceded VΔC by 10 to 20 seconds. CaV1.2 VΔC synergistically augmented signaling by N-methyl-d-aspartate receptors. Furthermore, VΔC mistuning correlated with autistic symptoms in Timothy syndrome. Thus, nonionic VΔC signaling is vital to the function of CaV1.2 in synaptic and neuropsychiatric processes.

Browsing by Subject "Synapses"

Background and purpose

Methods

Results

Conclusions