Inhibitory Synaptic Connections Research Articles

External excitatory stimuli can terminate bursting in neural network models

The concept of modulating or terminating seizure activity by brain stimulation is attracting considerable attention. The ability of such external excitatory stimuli to terminate repetitive bursting may depend upon identifiable parameters. We investigate the ability of external stimuli to terminate bursting under various conditions in defined neural network models. Networks of multiple neurons ( n=90), with both inhibitory and excitatory synaptic connections were modeled using conductance-based models with a reduced number of variables. Each neuron in the network has synaptic connections from randomly chosen excitatory and inhibitory neurons. The type and number of connections were kept constant. The initial parameters of the networks were chosen to simulate synchronized repetitive bursting activity. Two basic models of repetitive bursting activity were developed. The first model is a single network with constant random excitatory input, the second incorporates two networks with no random background input, but with a feedback loop with a delay of 600–900 ms connecting two networks. The ability of external excitatory stimuli to terminate repetitive bursting in each model was studied. External excitatory stimulation terminates repetitive bursting in both models; however, only in the models with a feedback loop, is the burst termination long-lasting. In the single network model with constant random excitatory input, termination is of short duration and recurrent bursting resumes. Timing of the application of the stimulus to the dual network model is critical; long-lasting termination occurs only when the stimuli to the first network are during a time when the connected network is still relatively refractory. The delay in the loop determines the exact timing of the stimulus. Synaptic inhibition is not required for burst termination. Neural network models provide systems for the study of burst termination and can help define the requirements for such stimuli to successfully terminate bursts. Studies in these models can guide the development and application of such stimuli in intact systems.

L-type calcium channel-mediated plateau potentials in barrelette cells during structural plasticity.

Development and maintenance of whisker-specific patterns along the rodent trigeminal pathway depends on an intact sensory periphery during the sensitive/critical period in development. Barrelette cells of the brain stem trigeminal nuclei are the first set of neurons to develop whisker-specific patterns. Those in the principal sensory nucleus (PrV) relay these patterns to the ventrobasal thalamus, and consequently, to the somatosensory cortex. Thus PrV barrelette cells are among the first group of central neurons susceptible to the effects of peripheral damage. Previously we showed that membrane properties of barrelette cells are distinct as early as postnatal day 1 (PND 1) and remain unchanged following peripheral denervation in newborn rat pups (Lo and Erzurumlu 2001). In the present study, we investigated the changes in synaptic transmission. In barrelette cells of normal PND 1 rats, weak stimulation of the trigeminal tract (TrV) that was subthreshold for inducing Na(+) spikes evoked an excitatory postsynaptic potential-inhibitory postsynaptic potential (EPSP-IPSP) sequence that was similar to the responses seen in older rats (Lo et al. 1999). Infraorbital nerve transection at birth did not alter excitatory and inhibitory synaptic connections of the barrelette cells. These observations suggested that local neuronal circuits are already established in PrV at birth and remain intact after deafferentation. Strong stimulation of the TrV induced a sustained depolarization (plateau potential) in denervated but not in normal barrelette neurons. The plateau potential was distinct from the EPSP-IPSP sequence by 1) a sustained (>80 ms) depolarization above -40 mV; 2) a slow decline slope (<0.1 mV/ms); 3) partially or totally inactivated Na(+) spikes on the plateau; and 4) a termination by a steep decay (>1 mV/ms) to a hyperpolarizing membrane level. The plateau potential was mediated by L-type Ca(2+) channels and triggered by a N-methyl-D-aspartate (NMDA) receptor-mediated EPSP. gamma-aminobutyric acid-A (GABA(A)) receptor-mediated IPSP dynamically regulated the latency and duration of the plateau potential. These results indicate that after neonatal peripheral damage, central trigeminal inputs cause a large and long-lasting Ca(2+) influx through L-type Ca(2+) channels in barrelette neurons. Increased Ca(2+) entry may play a key role in injury-induced structural remodeling, and/or transsynaptic cell death.

Phase-locked coordination between two rhythmically active feeding structures in the mollusk Clione limacina. I. Motor neurons.

Coordination between different motor centers is essential for the orderly production of all complex behaviors, in both vertebrates and invertebrates. The current study revealed that rhythmic activities of two feeding structures of the pteropod mollusk Clione limacina, radula and hooks, which are used to extract the prey from its shell, are highly coordinated in a phase-dependent manner. Hook protraction always coincided with radula retraction, while hook retraction coincided with radula protraction. Thus hooks and radula were always moving in the opposite phases, taking turns grabbing and pulling the prey tissue out of the shell. Identified buccal ganglia motor neurons controlling radula and hooks protraction and retraction were rhythmically active in the same phase-dependent manner. Hook protractor motor neurons were active in the same phase with radula retractor motor neurons, while hook retractor motor neurons burst in phase with radula protractor motor neurons. One of the main mechanisms underlying the phase-locked coordination was electrical coupling between hook protractor and radula retractor motor neurons. In addition, reciprocal inhibitory synaptic connections were found between hook protractor and radula protractor motor neurons. These electrical and inhibitory synaptic connections ensure that rhythmically active hooks and radula controlling motor neurons are coordinated in the specific phase-dependent manner described above. The possible existence of a single multifunctional central pattern generator for both radula and hook motor centers is discussed.

Cooperative endocannabinoid production by neuronal depolarization and group I metabotropic glutamate receptor activation

Endocannabinoids are retrograde messengers that are released from central neurons by depolarization-induced elevation of intracellular Ca2+ concentration [Ca2+]I or by activation of a group I metabotropic glutamate receptor (mGluR). We studied the interaction between these two pathways for endocannabinoid production in rat hippocampal neurons. We made a paired whole-cell recording from cultured hippocampal neurons with inhibitory synaptic connections. Activation of group I mGluRs, mainly mGluR5, by the specific agonist (RS)-3,5-dihydroxyphenylglycine (DHPG), suppressed inhibitory postsynaptic currents (IPSCs) in about half of the neuron pairs. A cannabinoid agonist, WIN55,212-2, suppressed IPSCs in all DHPG-sensitive pairs but not in most of DHPG-insensitive pairs. The effects of both DHPG and WIN55,212-2 were abolished by the cannabinoid antagonists, AM281 and SR141716A, indicating that activation of group I mGluR releases endocannabinoids and suppress inhibitory neurotransmitter release through activation of presynaptic cannabinoid receptors. Depolarization of the postsynaptic neurons caused a transient suppression of IPSCs, a phemomenon termed depolarization-induced suppression of inhibition (DSI) that was also abolished by cannabinoid antagonists. Importantly, DSI was enhanced significantly when group I mGluRs were activated simultaneously by DHPG. This enhancement was much more prominent than expected from the simple summation of depolarization-induced and group I mGluR-induced endocannabinoid release. DHPG caused no change in depolarization-induced Ca2+ transients, indicating that the enhanced DSI by DHPG was not due to the augmentation of Ca2+ influx. Enhancement of DSI by DHPG was also observed in hippocampal slices. These results suggest that two pathways work in a cooperative manner to release endocannabinoids via a common intracellular cascade.

A neural network model of the inferior colliculus with modifiable lateral inhibitory synapses for human echolocation.

We propose a neural network model of the inferior colliculus (IC) for human echolocation. Neuronal mechanisms for human echolocation were investigated by simulating the model. The model consists of the neural networks of the central nucleus (ICc) and external nucleus (ICx) of the inferior colliculus. The neurons of the ICc receive interaural sound stimuli via multiple contralateral delay lines and a single ipsilateral delay line. The neurons of the ICc send output signals to the neurons of the ICx in a convergent manner. We stimulated the ICc with pairs of a direct sound (a sonar sound) and an echo sound (the reflection from an object). Information about the distance between the model and the object is expressed by the delay time of the echo sound with respect to the direct sound. The results presented here show that neurons of the ICc responsive to interaural onset time differences contribute to the creation of an auditory distance map in the ICx. We trained the model with various pairs of direct-echo sounds and modified synaptic connection strengths of the networks according to the Hebbian rule. It is shown that self-organized long-term depression of lateral inhibitory synaptic connections plays an important role in enhancing echolocation skills.

Relationships of local inhibitory and excitatory circuits to orientation preference maps in ferret visual cortex.

The contribution and precise role of intracortical circuits in generating orientation tuned responses in visual cortical neurons is still controversial. To address this question, the relationship between excitatory and inhibitory synaptic connections and orientation maps in ferret striate cortex was investigated by combining in vivo optical imaging and in vitro scanning laser photostimulation. Excitatory and inhibitory inputs to pyramidal cells originated preferentially from regions with similar orientation preference. Prominent cross-orientation inhibition was not observed, arguing against cross-orientation models of orientation selectivity. The tuning of inhibitory inputs was significantly broader in both layer 2/3 and layer 5/6 pyramidal neurons compared to the tuning of excitatory inputs. Local excitatory inputs were more prominent in the 0-20 degrees tuning difference range between pre- and postsynaptic cells than inhibitory inputs, whereas inhibition dominated in the 20-40 degrees tuning difference range. These differences in tuning of excitatory and inhibitory inputs onto individual cells are consistent with the predictions of recurrent models of orientation selectivity.

Electrical Synapses in the Thalamic Reticular Nucleus

Neurons of the thalamic reticular nucleus (TRN) provide inhibitory input to thalamic relay cells and generate synchronized activity during sleep and seizures. It is widely assumed that TRN cells interact only via chemical synaptic connections. However, we show that many neighboring pairs of TRN neurons in rats and mice are electrically coupled. In paired-cell recordings, electrical synapses were able to mediate close correlations between action potentials when the coupling was strong; they could modulate burst-firing states even when the coupling strength was more modest. Electrical synapses between TRN neurons were absent in mice with a null mutation for the connexin36 (Cx36) gene. Surprisingly, inhibitory chemical synaptic connections between pairs of neurons were not observed, although strong extracellular stimuli could evoke inhibition in single TRN neurons. We conclude that Cx36-dependent gap junctions play an important role in the regulation of neural firing patterns within the TRN. When combined with recent observations from the cerebral cortex, our results imply that electrical synapses are a common mechanism for generating synchrony within networks of inhibitory neurons in the mammalian forebrain.

Estructura de la corteza cerebral. Organización intrínseca y análisis comparativo del neocórtex

Summary. We review our present knowledge on the intrinsic organization of the neocortex based on studies carried out with the Golgi method in several mammalian species. An outline is presented on certain general aspects of the termination of specific afferent fibers in layer IV in insectivora, rodents, carnivora and primates. The principal components of the cerebral cortex have been classifi ed in two broad types: pyramidal cells, which account for nearly 70% of the total population, and intrinsic neurons. We review dif ferent morphological characteristics of pyramidal cells and intrinsic neurons with a full description of cell varieties, dendritic mor phology and several aspects of synaptic connectivity of intrinsic neurons in comparison between different species. Special attention ha s been paid to the description of spinous stellate cells which seems unique for a given animal species. We have reviewed intrinsic cor tical circuits linking several neocortical layers, the distribution of dendritic plexuses, and the excitatory and inhibitory synaptic connections established between various neuronal categories. We finally review modern concepts of functional neocortical architecture based on the modular organization of the cerebral cortex, concluding that the cerebral cortex is rather uniform at en elementar y level but the differences appear substantial when the comparison is made between different species. [REV NEUROL 2002; 34: 758-80]

Epileptiform activity in a neocortical network: a mathematical model

A simple mathematical model describing the generation and propagation of epileptiform activity in a cerebral cortical network is presented. The model consists of a system of nonlinear delay differential equations. Physiological properties are taken into account as nonlinear transmission of signals at the synapse, temporal and spatial summation of incoming signals at the soma, active membrane characteristics, and dendritic and axonal propagation times. The influence of the connectivity and the temporal parameters on the oscillatory properties of the model is studied. The computer simulations are in agreement with experimental observations in cortical networks: whereas a weak excitatory or strong inhibitory synaptic connection strength produces a stationary status with short-lasting responses to external stimuli, increases in excitation or decreases in inhibition induce spontaneous and stimulus-evoked rhythmic discharges. Synaptic burst-like activity is observed only for an intermediate range of excitatory and inhibitory connection strengths and external inputs. The form and duration of the bursts can also be controlled by the temporal parameters. The results demonstrate that relatively simple mathematical equations are sufficient to model some of the network properties underlying the generation and propagation of epileptiform activity.

Slow IPSC kinetics, low levels of alpha1 subunit expression and paired-pulse depression are distinct properties of neonatal inhibitory GABAergic synaptic connections in the mouse superior colliculus.

Remodelling of visual maps in the superior colliculus (SC) depends on neuronal activity. Synaptic inhibition could contribute to this process because spontaneous spike discharge in the SC was modulated by GABA(A) receptor activation at postnatal days (P) 1-3. To investigate the functional capacity of GABAergic synaptic transmission at this early stage of development, whole-cell patch-clamp recordings were made from wide field neurons (WFNs) in horizontal slices comprising the superficial grey layer of the SC. Focal stimulation in the vicinity of WFNs evoked tetrodotoxin-sensitive stimulus-locked inhibitory postsynaptic currents (eIPSCs). The failure rate of eIPSCs was low ( approximately 0.2), and the maximal amplitude of evoked unitary eIPSCs exceeded the amplitude of average miniature IPSCs (mIPSCs) by a factor of 4-5, suggesting that action potential-mediated GABA release was more effective than spontaneous release. Some of the properties of GABAergic synaptic transmission in the neonatal SC were age-specific. In contrast with eIPSCs in the more mature SC at P20-22, neonatal eIPSCs decayed more slowly, preferentially fluctuated in duration, not amplitude, and mostly lacked temporal summation, due to depression at shorter intervals. The paired-pulse ratio (eIPSC2 : eIPSC1) was inversely related to the duration of eIPSCs. PCR analysis showed, in addition, that the ratio of alpha1 : alpha3 subunit expression was lower in the neonatal SC. Together, these results suggest that, at a young age, efficacy of GABAergic synaptic transmission is primarily constrained by the slow kinetics and the saturation of postsynaptic GABA(A) receptors.

Phase-coupled oscillator models can predict hippocampal inhibitory synaptic connections.

What factors are responsible for propagating electrical activity in the hippocampus? Using an intact, isolated hippocampus preparation, it is possible to observe spontaneous delta (< or = 4 Hz) waves of rhythmic field potentials. These rhythmic potentials are inhibitory in nature, mediated by GABAergic inhibitory potentials originating from a population of principal neurons. They start in the ventro-temporal region and move longitudinally towards the dorso-septal region with a phase lag of approximately 10% between the extracellular recordings. We use the mathematical framework of phase-coupled oscillators (PCO) to gain some insight into the underlying network system. A chain of 15 nearest-neighbour bidirectionally coupled PCOs is used where each oscillator refers to a segment of the CA1 region of the hippocampus that can generate these slow field potentials. We find that ventro-dorsal delta waves exist if there is a dominance in coupling strength in one direction. Without a one-way coupling dominance, ventro-dorsal waves can still exist, but then the coupling strengths need to be much larger. The relationship between entrained and intrinsic frequencies and the variation of propagation speeds along the longitudinal axis can be used to determine which case applies. Currently available experimental data supports one of the cases, predicting that there is a stronger ventral to dorsal inhibitory effect.

Endogenous Cannabinoids Mediate Retrograde Signals from Depolarized Postsynaptic Neurons to Presynaptic Terminals

Endogenous cannabinoids are considered to function as diffusible and short-lived modulators that may transmit signals retrogradely from postsynaptic to presynaptic neurons. To evaluate this possibility, we have made a paired whole-cell recording from cultured hippocampal neurons with inhibitory synaptic connections. In about 60% of pairs, a cannabinoid agonist greatly reduced the release of the inhibitory neurotransmitter GABA from presynaptic terminals. In most of such pairs but not in those insensitive to the agonist, depolarization of postsynaptic neurons and the resultant elevation of intracellular Ca 2+ concentration caused transient suppression of inhibitory synaptic currents, which is mainly due to reduction of GABA release. This depolarization-induced suppression was completely blocked by selective cannabinoid antagonists. Our results reveal that endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals to cause the reduction of transmitter release.

Activity-dependent modification of inhibitory synapses in models of rhythmic neural networks.

The faithful production of rhythms by many neural circuits depends critically on the strengths of inhibitory synaptic connections. We propose a model in which the strengths of inhibitory synapses in a central pattern-generating circuit are subject to activity-dependent plasticity. The strength of each synapse is modified as a function of the global activity of the postsynaptic neuron and by correlated activity of the pre- and postsynaptic neurons. This allows the self-assembly, from random initial synaptic strengths, of two cells into reciprocal oscillation and three cells into a rhythmic triphasic motor pattern. This self-assembly illustrates that complex oscillatory circuits that depend on multiple inhibitory synaptic connections can be tuned via simple activity-dependent rules.

Respiratory rhythm generation in neonatal and adult mammals: the hybrid pacemaker–network model

We review a new unified model of respiratory rhythm generation — the hybrid pacemaker–network model. This model represents a comprehensive synthesis of cellular and network mechanisms that can theoretically account for rhythm generation in different functional states, from the most reduced states in the neonatal nervous system in vitro to the intact adult system in vivo. The model incorporates a critical neuronal kernel consisting of a network of excitatory neurons with state-dependent, oscillatory bursting or pacemaker properties. This kernel, located in the pre-Bötzinger complex of the ventrolateral medulla, provides a rudimentary pacemaker network mechanism for generating an inspiratory rhythm, revealed predominately in functionally reduced states in vitro. In vivo the kernel is embedded in a larger network that interacts with the kernel via inhibitory synaptic connections that provide the dynamic control required for the evolution of the complete pattern of inspiratory and expiratory network activity. The resulting hybrid of cellular pacemaker and network properties functionally endows the system with multiple mechanisms of rhythm generation. New biophysically realistic mathematical models of the hybrid pacemaker–network have been developed that illustrate these concepts and provide a computational framework for investigating interactions of cellular and network processes that must be analyzed to understand rhythm generation.

Neocortical networks of pyramidal neurons: from local locking andchaosto macroscopic chaos and synchronization

We determine the properties of locking of inhibitory andof excitatory synaptic connections with neocortical pyramidal cells. Weareable to give anoverview of the emerging periodic behaviour, as a function of theperturbation strength. We show thata chaotic response emerges forinhibitory connections on an open set of positive measure of theparameterspace. This implies that synchronization on the set of inhibitoryconnectionsis possible, with positive probability.

Newly identified inhibitory synaptic connection from P-cell to RAR-cell in rat NTS

Newly identified inhibitory synaptic connection from P-cell to RAR-cell in rat NTS

A Pair of Reciprocally Inhibitory Histaminergic Sensory Neurons Are Activated within the Same Phase of Ingestive Motor Programs inAplysia

Previous studies have shown that each buccal ganglion in Aplysia contains two B52 neurons, one in each hemiganglion. We now show that there are two B52 neurons in a single buccal hemiganglion and four cells in an animal. We also show that the B52 neurons are histamine-immunoreactive and use reverse phase HPLC to show that the histamine-immunoreactive substance is authentic histamine. Previous studies have shown that the B52 neurons make numerous inhibitory synaptic connections with neurons active during the radula closing/retraction phase of ingestive motor programs. A computational model of the Aplysia feeding central pattern generator has, therefore, suggested that the B52 neurons play a role in terminating closing/retraction. Consistent with this idea we show that both B52 neurons fire at the beginning of radula opening/protraction. We also show that both B52 neurons are sensory neurons. They are depolarized when a flap of connective tissue adjacent to the buccal commissural arch is stretched. During ingestive feeding this is likely to occur at the peak of closing/retraction as opening/protraction begins. In the course of this study we compare the two ipsilateral B52 neurons and show that these cells are virtually indistinguishable; e.g., they use a common neurotransmitter, make the same synaptic connections, and are both sensory as well as premotor neurons. Nevertheless we show that the B52 neurons are reciprocally inhibitory. Our results, therefore, strikingly confirm theoretical predictions made by others that neurons that inhibit each other will not necessarily participate in antagonistic phases of behavior.

Synaptic currents at individual connections among stellate cells in rat cerebellar slices.

1. Unitary inhibitory synaptic connections among stellate cells were studied in rat cerebellar slices. Presynaptic action potentials and inhibitory postsynaptic currents (IPSCs) were simultaneously recorded by loose cell-attached and tight-seal whole-cell recording, respectively. 2. Several types of synaptic connections were distinguished on the basis of the shape of the amplitude distribution of successfully evoked currents. For simple synapses, which presumably arise at single release sites, these histograms could be fitted to a single Gaussian (5 cases). In four additional cases a small amplitude component (< 50 pA) was superimposed to a single Gaussian peak. The small events had slow rise times and widely distributed amplitudes. Finally eleven histograms showed two or more Gaussian components and were classified as complex connections. 3. Failure rates ranged from 0.06 to 0.85 for unitary connections (n = 20) and from 0.59 to 0.78 for simple synapses (n = 5). 4. Coefficient of variation values derived from Gaussian fits to simple synapse histograms ranged between 0.20 and 0.38 (n = 5). 5. In simple synapses peak current amplitudes were positively correlated to both current rise time and decay half-width. 6. Intervals between presynaptic action potentials were widely distributed. During stationary periods there was no correlation between interspike interval and amplitude size, success rate or latency. In some experiments, episodes with shorter interspike intervals were observed. During these periods, amplitude and success rate decreased, and the latency increased. Thus, IPSC characteristics depend on the mean frequency of presynaptic spikes, but not on random fluctuations of interspike intervals during stationary periods.

Inadequate cortical feature maps: A neural circuit theory of autism

The autistic syndromes are caused by neurological dysfunctions. The capacity of autistic individuals to form representations of previous sensory impressions, useful for the processing of present information, is impaired. Self-organizing feature maps are mathematical models of cortical feature maps and may be used to simulate cortical processing. Dysfunctional self-organization, resulting in disability to extract features from stimuli, is proposed as a neural circuit theory of autism. The nature and a possible cause of dysfunction self-organization are examined. It is shown that impaired feature detection is valid for explaining the memory function in autism, the lack of drive for central coherence according to Frith's theory of autism, and a number of impairments from the diagnostic criteria. Unequal levels of impairment of different cortical feature maps can account for the typically uneven intelligence profile of autistic individuals. Excessive inhibitory lateral feedback synaptic connection strengths are presented as one factor impairing the development of feature maps. Strong or excessive inhibitory lateral feedback synaptic connection strengths also cause high sensory discrimination and abnormal sensory responses, both documented in autism. A neural circuit theory for autism has been presented. For a proof of this neural circuit theory neurological investigations are required.

Glutamatergic N2v cells are central pattern generator interneurons of the lymnaea feeding system: new model for rhythm generation.

We aimed to show that the paired N2v (N2 ventral) plateauing cells of the buccal ganglia are important central pattern generator (CPG) interneurons of the Lymnaea feeding system. N2v plateauing is phase-locked to the rest of the CPG network in a slow oscillator (SO)-driven fictive feeding rhythm. The phase of the rhythm is reset by artificially evoked N2v bursts, a characteristic of CPG neurons. N2v cells have extensive input and output synaptic connections with the rest of the CPG network and the modulatory SO cell and cerebral giant cells (CGCs). Synaptic input from the protraction phase interneurons N1M (excitatory), N1L (inhibitory), and SO (inhibitory-excitatory) are likely to contribute to a ramp-shaped prepotential that triggers the N2v plateau. The prepotential has a highly complex waveform due to progressive changes in the amplitude of the component synaptic potentials. Most significant is the facilitation of the excitatory component of the SO --> N2v monosynaptic connection. None of the other CPG interneurons has the appropriate input synaptic connections to terminate the N2v plateaus. The modulatory function of acetylcholine (ACh), the transmitter of the SO and N1M/N1Ls, was examined. Focal application of ACh (50-ms pulses) onto the N2v cells reproduced the SO --> N2v biphasic synaptic response but also induced long-term plateauing (20-60 s). N2d cells show no endogenous ability to plateau, but this can be induced by focal applications of ACh. The N2v cells inhibit the N3 tonic (N3t) but not the N3 phasic (N3p) CPG interneurons. The N2v --> N3t inhibitory synaptic connection is important in timing N3t activity. The N3t cells recover from this inhibition and fire during the swallow phase of the feeding pattern. Feedback N2v inhibition to the SO, N1L protraction phase interneurons prevents them firing during the retraction phase of the feeding cycle. The N2v --> N1M synaptic connection was weak and only found in 50% of preparations. A weak N2v --> CGC inhibitory connection prevents the CGCs firing during the rasp (N2) phase of the feeding cycle. These data allowed a new model for the Lymnaea feeding CPG to be proposed. This emphasizes that each of the six types of CPG interneuron has a unique set of synaptic connections, all of which contribute to the generation of a full CPG pattern.