Maternal loss of Ube3a produces an excitatory/inhibitory imbalance through neuron type-specific synaptic defects

Angelman syndrome (AS) is a neurodevelopmental disorder caused by loss of the maternally inherited allele of UBE3A. AS model mice, which carry a maternal Ube3a null mutation (Ube3a(m-/p+)), recapitulate major features of AS in humans, including enhanced seizure susceptibility. Excitatory neurotransmission onto neocortical pyramidal neurons is diminished in Ube3a(m-/p+) mice, seemingly at odds with enhanced seizure susceptibility. We show here that inhibitory drive onto neocortical pyramidal neurons is more severely decreased in Ube3a(m-/p+) mice. This inhibitory deficit follows the loss of excitatory inputs and appears to arise from defective presynaptic vesicle cycling in multiple interneuron populations. In contrast, excitatory and inhibitory synaptic inputs onto inhibitory interneurons are largely normal. Our results indicate that there are neuron type-specific synaptic deficits in Ube3a(m-/p+) mice despite the presence of Ube3a in all neurons. These deficits result in excitatory/inhibitory imbalance at cellular and circuit levels and may contribute to seizure susceptibility in AS.     

Transient bifurcations in neural error correction

This paper presents an investigation into the responses of neurons to errors in presynaptic spike trains. Errors are viewed, in nonlinear dynamical terms, as brief-duration changes in stationary presynaptic spike trains which induce transient responses in the postsynaptic cell. As these are generally large-magnitude transients, linearized neural models are not helpful. Instead, the responses of a full, nonlinear physiological model of a neuron that includes the recognized living prototype of an inhibitory synapse are analyzed. More specifically, the transients are examined in the context of the stationary behaviors that precede and succeed each error. It is shown that one and two dimensional bifurcation diagrams can be constructed from the transient responses--that there are marked changes in the transient responses at points that correspond to bifurcations in the stationary responses, qualitative changes in transients on either side of bifurcations, and only quantitative changes in transients between bifurcations.     

High-frequency oscillations and sequence generation in two-population models of hippocampal region CA1

Hippocampal sharp wave/ripple oscillations are a prominent pattern of collective activity, which consists of a strong overall increase of activity with superimposed (140 − 200 Hz) ripple oscillations. Despite its prominence and its experimentally demonstrated importance for memory consolidation, the mechanisms underlying its generation are to date not understood. Several models assume that recurrent networks of inhibitory cells alone can explain the generation and main characteristics of the ripple oscillations. Recent experiments, however, indicate that in addition to inhibitory basket cells, the pattern requires in vivo the activity of the local population of excitatory pyramidal cells. Here, we study a model for networks in the hippocampal region CA1 incorporating such a local excitatory population of pyramidal neurons. We start by investigating its ability to generate ripple oscillations using extensive simulations. Using biologically plausible parameters, we find that short pulses of external excitation triggering excitatory cell spiking are required for sharp/wave ripple generation with oscillation patterns similar to in vivo observations. Our model has plausible values for single neuron, synapse and connectivity parameters, random connectivity and no strong feedforward drive to the inhibitory population. Specifically, whereas temporally broad excitation can lead to high-frequency oscillations in the ripple range, sparse pyramidal cell activity is only obtained with pulse-like external CA3 excitation. Further simulations indicate that such short pulses could originate from dendritic spikes in the apical or basal dendrites of CA1 pyramidal cells, which are triggered by coincident spike arrivals from hippocampal region CA3. Finally we show that replay of sequences by pyramidal neurons and ripple oscillations can arise intrinsically in CA1 due to structured connectivity that gives rise to alternating excitatory pulse and inhibitory gap coding; the latter denotes phases of silence in specific basket cell groups, which induce selective disinhibition of groups of pyramidal neurons. This general mechanism for sequence generation leads to sparse pyramidal cell and dense basket cell spiking, does not rely on synfire chain-like feedforward excitation and may be relevant for other brain regions as well.     

Emergence of oscillations in a model of weakly coupled two Bonhoeffer-van der Pol equations

Bifurcations of periodic solutions in a model of weakly coupled two Bonhoeffer-van der Pol equations are studied. The model realizes a half-center model with reciprocal inhibition, a typical model used in the field of neural motor control to account for the generation of alternating rhythmic bursts observed in motoneurons and spinal neural networks. Several oscillatory solutions such as in-phase, anti-phase as well as out-of-phase solutions emerge from the model's equilibrium as one of the parameters of the model changes. Among the variety of bifurcations exhibited by the model, we analyze Hopf bifurcations, by which several periodic solutions emerge, and illustrate generation mechanisms of alternating oscillations in the model.     

Temporal redistribution of inhibition over neuronal subcellular domains underlies state-dependent rhythmic change of excitability in the hippocampus

The behaviour-contingent rhythmic synchronization of neuronal activity is reported by local field potential oscillations in the theta, gamma and sharp wave-related ripple (SWR) frequency ranges. In the hippocampus, pyramidal cell assemblies representing temporal sequences are coordinated by GABAergic interneurons selectively innervating specific postsynaptic domains, and discharging phase locked to network oscillations. We compare the cellular network dynamics in the CA1 and CA3 areas recorded with or without anaesthesia. All parts of pyramidal cells, except the axon initial segment, receive GABA from multiple interneuron types, each with distinct firing dynamics. The axon initial segment is exclusively innervated by axo-axonic cells, preferentially firing after the peak of the pyramidal layer theta cycle, when pyramidal cells are least active. Axo-axonic cells are inhibited during SWRs, when many pyramidal cells fire synchronously. This dual inverse correlation demonstrates the key inhibitory role of axo-axonic cells. Parvalbumin-expressing basket cells fire phase locked to field gamma activity in both CA1 and CA3, and also strongly increase firing during SWRs, together with dendrite-innervating bistratified cells, phasing pyramidal cell discharge. Subcellular domain-specific GABAergic innervation probably developed for the coordination of multiple glutamatergic inputs on different parts of pyramidal cells through the temporally distinct activity of GABAergic interneurons, which differentially change their firing during different network states.     

Subunit composition of kainate receptors in hippocampal interneurons

Kainate receptor activation affects GABAergic inhibition in the hippocampus by mechanisms that are thought to involve the GluR5 subunit. We report that disruption of the GluR5 subunit gene does not cause the loss of functional KARs in CA1 interneurons, nor does it prevent kainate-induced inhibition of evoked GABAergic synaptic transmission onto CA1 pyramidal cells. However, KAR function is abolished in mice lacking both GluR5 and GluR6 subunits, indicating that KARs in CA1 stratum radiatum interneurons are heteromeric receptors composed of both subunits. In addition, we show the presence of presynaptic KARs comprising the GluR6 but not the GluR5 subunit that modulate synaptic transmission between inhibitory interneurons. The existence of two separate populations of KARs in hippocampal interneurons adds to the complexity of KAR localization and function.     

Presynaptic NMDA receptors mediate IPSC potentiation at GABAergic synapses in developing rat neocortex

Background

NMDA receptors are traditionally viewed as being located postsynaptically, at both synaptic and extrasynaptic locations. However, both anatomical and physiological studies have indicated the presence of NMDA receptors located presynaptically. Physiological studies of presynaptic NMDA receptors on neocortical GABAergic terminals and their possible role in synaptic plasticity are lacking.

Methodology/Principal Findings

We report here that presynaptic NMDA receptors are present on GABAergic terminals in developing (postnatal day (PND) 12-15) but not older (PND21-25) rat frontal cortex. Using MK-801 in the recording pipette to block postsynaptic NMDA receptors, evoked and miniature IPSCs were recorded in layer II/III pyramidal cells in the presence of AMPA/KA receptor antagonists. Bath application of NMDA or NMDA receptor antagonists produced increases and decreases in mIPSC frequency, respectively. Physiologically patterned stimulation (10 bursts of 10 stimuli at 25 Hz delivered at 1.25 Hz) induced potentiation at inhibitory synapses in PND12-15 animals. This consisted of an initial rapid, large increase in IPSC amplitude followed by a significant but smaller persistent increase. Similar changes were not observed in PND21-25 animals. When 20 mM BAPTA was included in the recording pipette, potentiation was still observed in the PND12-15 group indicating that postsynaptic increases in calcium were not required. Potentiation was not observed when patterned stimulation was given in the presence of D-APV or the NR2B subunit antagonist Ro25-6981.

Conclusions/Significance

The present results indicate that presynaptic NMDA receptors modulate GABA release onto neocortical pyramidal cells. Presynaptic NR2B subunit containing NMDA receptors are also involved in potentiation at developing GABAergic synapses in rat frontal cortex. Modulation of inhibitory GABAergic synapses by presynaptic NMDA receptors may be important for proper functioning of local cortical networks during development.     

High codimensional bifurcation analysis to a six-neuron BAM neural network

In this article, the high codimension bifurcations of a six-neuron BAM neural network system with multiple delays are addressed. We first deduce the existence conditions under which the origin of the system is a Bogdanov–Takens singularity with multiplicities two or three. By choosing the connection coefficients as bifurcation parameters and using the formula derived from the normal form theory and the center manifold, the normal forms of Bogdanov–Takens and triple zero bifurcations are presented. Some numerical examples are shown to support our main results.     

The dynamics of two-species allelopathic competition with optimal harvesting

This paper analyses a bionomic model of two competitive species in the presence of toxicity with different harvesting efforts. An interesting dynamics in the first quadrant is analysed and two saddle-node bifurcations are detected for different bifurcation parameters. It is noted that under certain parametric restrictions, the model has a unique positive equilibrium point that is globally asymptotically stable whenever it is locally stable. It is also noted that the model can have zero, one or two feasible equilibria appearing through saddle-node bifurcations. The non-existence of a limit cycle in the interior of the first quadrant is also discussed using the Poincare–Dulac criteria. The saddle-node bifurcations are studied using Sotomayor's theorem. Numerical simulations are carried out to validate the analytical findings. The conditions for the existence of bionomic equilibria are discussed and an optimal harvesting policy is derived using Pontryagin's maximum principle.     

Complex events initiated by individual spikes in the human cerebral cortex

Synaptic interactions between neurons of the human cerebral cortex were not directly studied to date. We recorded the first dataset, to our knowledge, on the synaptic effect of identified human pyramidal cells on various types of postsynaptic neurons and reveal complex events triggered by individual action potentials in the human neocortical network. Brain slices were prepared from nonpathological samples of cortex that had to be removed for the surgical treatment of brain areas beneath association cortices of 58 patients aged 18 to 73 y. Simultaneous triple and quadruple whole-cell patch clamp recordings were performed testing mono- and polysynaptic potentials in target neurons following a single action potential fired by layer 2/3 pyramidal cells, and the temporal structure of events and underlying mechanisms were analyzed. In addition to monosynaptic postsynaptic potentials, individual action potentials in presynaptic pyramidal cells initiated long-lasting (37 ± 17 ms) sequences of events in the network lasting an order of magnitude longer than detected previously in other species. These event series were composed of specifically alternating glutamatergic and GABAergic postsynaptic potentials and required selective spike-to-spike coupling from pyramidal cells to GABAergic interneurons producing concomitant inhibitory as well as excitatory feed-forward action of GABA. Single action potentials of human neurons are sufficient to recruit Hebbian-like neuronal assemblies that are proposed to participate in cognitive processes.     

The dynamics of two-species allelopathic competition with optimal harvesting

This paper analyses a bionomic model of two competitive species in the presence of toxicity with different harvesting efforts. An interesting dynamics in the first quadrant is analysed and two saddle-node bifurcations are detected for different bifurcation parameters. It is noted that under certain parametric restrictions, the model has a unique positive equilibrium point that is globally asymptotically stable whenever it is locally stable. It is also noted that the model can have zero, one or two feasible equilibria appearing through saddle-node bifurcations. The non-existence of a limit cycle in the interior of the first quadrant is also discussed using the Poincare-Dulac criteria. The saddle-node bifurcations are studied using Sotomayor's theorem. Numerical simulations are carried out to validate the analytical findings. The conditions for the existence of bionomic equilibria are discussed and an optimal harvesting policy is derived using Pontryagin's maximum principle.     

Modulation of presynaptic store calcium induces release of glutamate and postsynaptic firing

Action potential-independent transmitter release is random and produces small depolarizations in the postsynaptic neuron. This process is, therefore, not thought to play a significant role in impulse propagation across synapses. Here we show that calcium flux through presynaptic neuronal nicotinic receptors leads to mobilization of store calcium by calcium-induced calcium release. Recruitment of store calcium induces vesicular release of glutamate in a manner consistent with synchronization across multiple active zones in the CA3 region of the rat hippocampus. This modulation of action potential-independent release of glutamate is sufficient to drive the postsynaptic pyramidal cell above its firing threshold, thus providing a mechanism for impulse propagation.     

Gaba sensitivity of the somata and dendrites of pyramidal cells in isolated slices of rat hippocampus

During experiments on isolated slices slices of rat hippocampus the inhibitory action of -aminobutyric acid (GABA) was investigated on the excitation of field CA, pyramidal neurons, together with the effects of bicuculline, penicillin and thiopentone on this process. It was found that GABA effectively and reversibly reduced the amplitude of the antrodomic population spike in the area of both the somata and the dendrites of these cells. The sensitivity of apical dendrites to GABA exceeded that of the somata by one order, increasing in a proximal-distal direction. The somata of pyramidal neurons were marked by pronounced desensitization to GABA. Bicuculline and penicillin acted as GABA antagonists at all the levels of CA, pyramidal cells investigated. Bicuculline blocked the effects of GABA on somata and dendrites in almost equal measure. The antagonistic effects of penicillin were 10 times greater in the pyramidal layer than in the dendritic region. Thiopentone reinforced the inhibitory effects of GABA. The potentiating effects of thiopentone were exerted most strongly on the dendrites. It is postulated that the membrane of field CA, neurons contain two types of bicuculline-sensitive GABA receptors, differing in their location (mainly on the cell body or dendrite), their pharmacology, and degree of desensitization to GABA.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 17, No. 6, pp. 737–746, November–December, 1985.     

Interacting Presynaptic k-Opioid and GABAA Receptors Modulate Dopamine Release from Rat Striatal Synaptosomes

Abstract— The presynaptic regulation of stimulated dopa-mine release from superfused rat striatal synaptosomes by opioids and γ-aminobutyric acid (GABA) was studied. It was found that in addition to dopamine D₂ autoreceptors, calcium-dependent K⁺-stimulated [³H]dopamine release was inhibited through activation of a homogeneous population of k -opioid receptors in view of the potent inhibitory effect of the k -selective agonist U69.593 (EC₅₀ 0.2 nM) and its antagonism by norbinaltorphimine. Neither μ-nor δ-selective receptor agonists affected release of [³H]-dopamine. In addition, GABA potently inhibited the evoked [³H]dopamine release (EC₅₀ 0.4 nM) through activation of GABA_A receptors in view of the GABA-mimicking effect of muscimol, the sensitivity of its inhibitory effect to picro-toxin and bicuculline, and the absence of an effect of the GABA_B receptor agonist baclofen. In the presence of a maximally effective concentration of GABA, U69,593 did not induce an additional release-inhibitory effect, indicating that these receptors and the presynaptic D₂ receptor are colocalized on the striatal dopaminergic nerve terminals. The excitatory amino acid agonists N-methyl-d -aspartate and kainate, as well as the cholinergic agonist carbachol, stimulated [³H]dopamine release, which was subject to k -opioid receptor-mediated inhibition. In conclusion, striatal dopamine release is under regulatory control of multiple excitatory and inhibitory neurotransmitter by activation of colocalized presynaptic receptors for excitatory amino acids, acetylcholine, dopamine, dynorphins, and GABA within the dopaminergic nerve terminals. Together, these receptors locally control ongoing dopamine neurotransmission.     

Synaptic localization of adrenergic disinhibition in the rat hippocampus.

Norepinephrine is an endogenous neurotransmitter that reduces synaptic inhibition onto pyramidal neurons in the hippocampus by an action at an alpha-adrenergic receptor. The physiological mechanism of this disinhibition was previously not known, except that it occurred at a site presynaptic to the inhibited pyramidal cell. In this paper we present evidence that adrenergic disinhibition is restricted to the early phase of the evoked inhibitory postsynaptic potential in area CA1 of the hippocampus. The locus of disinhibition does not appear to reside in the interneuronal terminal, axon, or cell body. Instead, adrenergic agonists appear to reduce evoked synaptic inhibition by depressing excitatory synapses that activate the interneuron.     

Separable models in age-dependent population dynamics

A class of population models is considered in which the parameters such as fecundity, mortality and interaction coefficients are assumed to be age-dependent. Conditions for the existence, stability and global attractivity of steady-state and periodic solutions are derived. The dependence of these solutions on the maturation periods is analyzed. These results are applied to specific single and multiple population models. It is shown that periodic solutions cannot occur in a general class of single population age-dependent models. Conditions are derived that determine whether increasing the maturation period has a stabilizing effect. In specific cases, it is shown that any number of switches in stability can occur as the maturation period is increased. An example is given of predator-prey model where each one of these stability switches corresponds to a stable steady state losing its stability via a Hopf bifurcation to a periodic solution and regaining its stability upon further increase of the maturation period.     

具有三时滞Lotka-Volterra互惠系统的Hopf分支

建立了具有三个时滞的Lotka-Volterra互惠系统;获得了正平衡点和Hopf分支存在的条件等;并对所获得的结果进行了数值模拟．     

Ionic Basis of Inhibitory Presynaptic Modulation in Rat Cortical Synaptosomes

We have investigated the possibility that, regardless of the involvement of a second messenger system, the ultimate effect of presynaptic, receptor-activated inhibitory modulation is the opening of a K channel. With the consequent hyperpolarization of the terminal, less Ca2+ would enter and this would result in the observed diminished release of a neurotransmitter. This possibility was explored utilizing rat cortical synaptosomes that were prelabeled with either 86Rb or [3H]acetylcholine, depolarizing with either K+ or veratridine, and measuring either efflux of 86Rb or release of [3H]acetylcholine in the presence or absence of inhibitory presynaptic modulators. The modulating agents used were 2-chloroadenosine, carbamylcholine, clonidine, and morphine. In all instances, these agents promoted an increased efflux of 86Rb, indicating hyperpolarization, and decreased release of acetylcholine. These results are compatible with our suggestion that an increase in K conductance may be responsible for presynaptic inhibition of the release of neurotransmitters.     

Cyclic AMP-dependent protein kinase phosphorylates group III metabotropic glutamate receptors and inhibits their function as presynaptic receptors

Recent evidence suggests that the functions of presynaptic metabotropic glutamate receptors (mGluRs) are tightly regulated by protein kinases. We previously reported that cAMP-dependent protein kinase (PKA) directly phosphorylates mGluR2 at a single serine residue (Ser843) on the C-terminal tail region of the receptor, and that phosphorylation of this site inhibits coupling of mGluR2 to GTP-binding proteins. This may be the mechanism by which the adenylyl cyclase activator forskolin inhibits presynaptic mGluR2 function at the medial perforant path-dentate gyrus synapse. We now report that PKA also directly phosphorylates several group III mGluRs (mGluR4a, mGluR7a, and mGluR8a), as well as mGluR3 at single conserved serine residues on their C-terminal tails. Furthermore, activation of PKA by forskolin inhibits group III mGluR-mediated responses at glutamatergic synapses in the hippocampus. Interestingly, beta-adrenergic receptor activation was found to mimic the inhibitory effect of forskolin on both group II and III mGluRs. These data suggest that a common PKA-dependent mechanism may be involved in regulating the function of multiple presynaptic group II and group III mGluRs. Such regulation is not limited to the pharmacological activation of adenylyl cyclase but can also be elicited by the stimulation of endogenous G(s)-coupled receptors, such as beta-adrenergic receptors.