Ionic mechanisms of endogenous bursting in CA3 hippocampal pyramidal neurons: a model study

A critical property of some neurons is burst firing, which in the hippocampus plays a primary role in reliable transmission of electrical signals. However, bursting may also contribute to synchronization of electrical activity in networks of neurons, a hallmark of epilepsy. Understanding the ionic mechanisms of bursting in a single neuron, and how mutations associated with epilepsy modify these mechanisms, is an important building block for understanding the emergent network behaviors. We present a single-compartment model of a CA3 hippocampal pyramidal neuron based on recent experimental data. We then use the model to determine the roles of primary depolarizing currents in burst generation. The single compartment model incorporates accurate representations of sodium (Na(+)) channels (Na(V)1.1) and T-type calcium (Ca(2+)) channel subtypes (Ca(V)3.1, Ca(V)3.2, and Ca(V)3.3). Our simulations predict the importance of Na(+) and T-type Ca(2+) channels in hippocampal pyramidal cell bursting and reveal the distinct contribution of each subtype to burst morphology. We also performed fast-slow analysis in a reduced comparable model, which shows that our model burst is generated as a result of the interaction of two slow variables, the T-type Ca(2+) channel activation gate and the Ca(2+)-dependent potassium (K(+)) channel activation gate. The model reproduces a range of experimentally observed phenomena including afterdepolarizing potentials, spike widening at the end of the burst, and rebound. Finally, we use the model to simulate the effects of two epilepsy-linked mutations: R1648H in Na(V)1.1 and C456S in Ca(V)3.2, both of which result in increased cellular excitability.     

Optogenetics reveals paradoxical network stabilizations in hippocampal CA1 and CA3

1. Download : Download high-res image (138KB)
2. Download : Download full-size image

     

Associative recognition and storage in a model network of physiological neurons

We consider a neural network model in which the single neurons are chosen to closely resemble known physiological properties. The neurons are assumed to be linked by synapses which change their strength according to Hebbian rules on a short time scale (100ms). The dynamics of the network — the time evolution of the cell potentials and the synapses — is investigated by computer simulation. As in more abstract network models (Cooper 1973; Hopfield 1982; Kohonen 1984) it is found that the local dynamics of the cell potentials and the synaptic strengths result in global cooperative properties of the network and enable the network to process an incoming flux of information and to learn and store patterns associatively. A trained net can associate missing details of a pattern, can correct wrong details and can suppress noise in a pattern. The network can further abstract the prototype from a series of patterns with variations. A suitable coupling constant connecting the dynamics of the cell potentials with the synaptic strengths is derived by a mean field approximation. This coupling constant controls the neural sensitivity and thereby avoids both extremes of the network state, the state of permanent inactivity and the state of epileptic hyperactivity.     

Fluctuation-driven rhythmogenesis in an excitatory neuronal network with slow adaptation

We study an excitatory all-to-all coupled network of N spiking neurons with synaptically filtered background noise and slow activity-dependent hyperpolarization currents. Such a system exhibits noise-induced burst oscillations over a range of values of the noise strength (variance) and level of cell excitability. Since both of these quantities depend on the rate of background synaptic inputs, we show how noise can provide a mechanism for increasing the robustness of rhythmic bursting and the range of burst frequencies. By exploiting a separation of time scales we also show how the system dynamics can be reduced to low-dimensional mean field equations in the limit N → ∞. Analysis of the bifurcation structure of the mean field equations provides insights into the dynamical mechanisms for initiating and terminating the bursts.     

An integrate-and-fire model for synchronized bursting in a network of cultured cortical neurons

It has been suggested that spontaneous synchronous neuronal activity is an essential step in the formation of functional networks in the central nervous system. The key features of this type of activity consist of bursts of action potentials with associated spikes of elevated cytoplasmic calcium. These features are also observed in networks of rat cortical neurons that have been formed in culture. Experimental studies of these cultured networks have led to several hypotheses for the mechanisms underlying the observed synchronized oscillations. In this paper, bursting integrate-and-fire type mathematical models for regular spiking (RS) and intrinsic bursting (IB) neurons are introduced and incorporated through a small-world connection scheme into a two-dimensional excitatory network similar to those in the cultured network. This computer model exhibits spontaneous synchronous activity through mechanisms similar to those hypothesized for the cultured experimental networks. Traces of the membrane potential and cytoplasmic calcium from the model closely match those obtained from experiments. We also consider the impact on network behavior of the IB neurons, the geometry and the small world connection scheme. Action Editor: David Golomb     

Simulations of a ventrolateral medullary neural network for respiratory rhythmogenesis inferred from spike train cross-correlation

Connections among ventrolateral medullary respiratory neurons inferred from spike train analysis were incorporated into a model and simulated with the program SYSTM11 (MacGregor 1987). Inspiratory (I) and expiratory (E) neurons with augmenting (AUG) and decrementing (DEC) discharge patterns and rostral I-E/I neurons exhibited varying degrees of adaptation, but no endogenous bursting properties. Simulation parameters were adjusted so that respiratory phase durations, neuronal discharge patterns, and short-time scale correlations were similar to corresponding measurements from anesthetized, vagotomized, adult cats. Rhythmogenesis persisted when the strength of each set of connections was increased 100% over a smaller effective value. Changes in phase durations and discharge patterns caused by manipulation of connection strengths or population activity led to several predictions. (a) Excitation of the I-E/I population prolongs the inspiratory phase. (b) Rhythmic activity can be reestablished in the absence of I-E/I activity by unpatterned excitation of I-DEC and I-AUG neurons. (c) An increase in I-DEC neuron activity can cause an apneustic respiratory pattern. (d) A decrease in I-DEC neuron activity increases the slope of the inspiratory ramp and shortens inspiration. (e) Excitation of the E-DEC population prolongs the expiratory phase or produces apnea; inhibition of E-DEC neurons reduces expiratory time. (f) Excitation of E-AUG cells causes I-AUG neurons to exhibit a step rather than a ramp increase in firing rate at the onset of their active phase. The results suggest mechanisms by which the duration of each phase of breathing and neuronal discharge patterns may be regulated. Received: 24 February 1993/Accepted in revised form: 8 September 1993     

Hyperpolarizing potentials in guinea pig hippocampal CA3 neurons

There is a bewildering variety of hyperpolarizing potentials which control activity in hippocampal pyramidal cells. These include an inhibitory postsynaptic potential (IPSP) with early and late components, voltage- and calcium-dependent potassium conductances, a voltage-dependent potassium conductance modulated by muscarinic agents (the M-current), and a complex and poorly understood afterhyperpolarization following epileptiform bursts. In hippocampal CA3 pyramidal cells, mossy fiber stimulation elicits an IPSP which is made up of two readily separable components. Using the in vitro slice preparation, we investigated the underlying ionic basis of these IPSP components and compared them to other hyperpolarizing potentials characteristic of the CA3 neurons. Intracellular recordings were obtained and then tissue was exposed to bathing medium low in chloride concentration or high in potassium concentration; the ion "blockers" EGTA (intracellular); tetraethylammonium (TEA) (intra- and extracellular), and barium and cobalt (extracellular); and the gamma-aminobutyric acid (GABA)/chloride antagonists penicillin, bicuculline and picrotoxin.     

Activity dynamics and behavioral correlates of CA3 and CA1 hippocampal pyramidal neurons

The CA3 and CA1 pyramidal neurons are the major principal cell types of the hippocampus proper. The strongly recurrent collateral system of CA3 cells and the largely parallel-organized CA1 neurons suggest that these regions perform distinct computations. However, a comprehensive comparison between CA1 and CA3 pyramidal cells in terms of firing properties, network dynamics, and behavioral correlations is sparse in the intact animal. We performed large-scale recordings in the dorsal hippocampus of rats to quantify the similarities and differences between CA1 (n > 3,600) and CA3 (n > 2,200) pyramidal cells during sleep and exploration in multiple environments. CA1 and CA3 neurons differed significantly in firing rates, spike burst propensity, spike entrainment by the theta rhythm, and other aspects of spiking dynamics in a brain state-dependent manner. A smaller proportion of CA3 than CA1 cells displayed prominent place fields, but place fields of CA3 neurons were more compact, more stable, and carried more spatial information per spike than those of CA1 pyramidal cells. Several other features of the two cell types were specific to the testing environment. CA3 neurons showed less pronounced phase precession and a weaker position versus spike-phase relationship than CA1 cells. Our findings suggest that these distinct activity dynamics of CA1 and CA3 pyramidal cells support their distinct computational roles.     

Stress early in life leads to cognitive impairments,reduced numbers of CA3 neurons and altered maternal behavior in adult female mice

The hippocampus is a crucial part of the limbic system involved both in cognitive processing and in the regulation of responses to stress. Adverse experiences early in life can disrupt hippocampal development and lead to impairment of the hypothalamic‐pituitary‐adrenal axis response to subsequent stressors. In our study, two types of early‐life stress were used: prolonged separation of pups from their mothers (for 3 hours/day, maternal separation, MS) and brief separation (for 15 minutes/day, handling, HD). In the first part of our study, we found that adult female mice (F0) who had experienced MS showed reduced locomotor activity and impairment of long‐term spatial and recognition memory. Analysis of various hippocampal regions showed that MS reduced the number of mature neurons in CA3 of females, which is perhaps a crucial hippocampal region for learning and memory; however, neurogenesis remained unchanged. In the second part, we measured maternal care in female mice with a history of early‐life stress (F0) as well as the behavior of their adult offspring (F1). Our results indicated that MS reduced the level of maternal care in adult females (F0) toward their own progeny and caused sex‐specific changes in the social behavior of adult offspring (F1). In contrast to MS, HD had no influence on female behavior or hippocampal plasticity. Overall, our results suggest that prolonged MS early in life affects the adult behavior of F0 female mice and hippocampal neuronal plasticity, whereas the mothers' previous experience has effects on the behavior of their F1 offspring through disturbances of mother‐infant interactions.     

Intrinsic neurons in the human ovary

Mammalian ovarian function is regulated by both hormonal inputs and direct neural influences. Recent studies have shown that, in addition to the extrinsic innervation, the ovaries of nonhuman primates and a strain of rats contain a discrete population of intrinsic neurons. In the present study, we used histological and immunohistochemical approaches to identify the presence of neuronal cell bodies in the fetal and neonatal human ovary. Neurons containing neurofilament immunoreactivity were detected in the hilum and medulla of the ovary at all ages studied, ranging from 24 weeks of gestation to 10 months of postnatal age. Most of them coexpressed the low affinity neurotrophin receptor (p75NTR), and some were catecholaminergic, as determined by their content of immunoreactive tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis. The presence of intrinsic neurons in the human ovary, similar to those previously found in other species, indicates that they may be engaged in regulating common, phylogenetically conserved, ovarian functions. It also raises the possibility that their dysfunction may contribute to the manifestation of particular ovarian pathologies.     

Passive cable properties of hippocampal CA3 pyramidal neurons

The passive electrical cable properties of CA3 pyramidal neurons from guinea pig hippocampal slices were investigated by applying current steps and recording the voltage transients from 25 CA3 neurons, using a single intracellular microelectrode and a 3-kHz time-share system. Two independent methods were used for estimating the equivalent electrotonic length of the dendrites, L, and the dendritic to somatic conductance ratio, . The first method is similar to that used by Gorman and Mirolli (1972) and gave an average L of 0.96; the average was 2.44. The second method is derived here for the first time and assumes a finite-length cable with lumped soma. It is an exact solution for L and , using the slopes and intercepts of the first two peeled exponentials. The average L was 0.94; the average was 1.51. The results, using both methods, are in close agreement. The average membrane time constant for all 25 CA3 neurons was 23.6 ms, suggesting a large (23,600 cm²) average membrane resistivity. It is concluded that CA3 neurons are electronically short.This work was supported by Grants NS 11535 and NS 15772 from the National Institute of Neurological and Communicative Disorders and Stroke, National Institutes of Health, U.S. Public Health Service.     

前包钦格复合体:产生呼吸节律的关键部位

呼吸节律的产生部位和原理一直是神经生物学研究领域中的热门课题。近年来的研究表明,延髓中一个被称为前包钦格复合体（pre-Botzinger complex,PBC)的区域在哺乳动物呼吸节律的产生中起着关键作用。本文主要介绍PBC的定位;PBC内呼吸神经元的类型及轴突投射;调节PBC呼吸神经元活动的神经递质;PBC参与呼吸节律形成的机制。     

Regulatory influence of hippocampus CA1 and CA3 areas on bulbar respiratory neurons under hypoxia

We studied the influence of stimulation of the CA1 and CA3 areas of the hippocampus on the impulse activity of respiratory neurons (RN) of the medulla oblongata under normal and oxygen deficiency conditions. Under conditions of normal atmospheric pressure, the electrical stimulation of the CA1 and CA3 areas of the hippocampus had mainly an inhibiting influence. In the initial phase, at a 4-5-thousand meter altitude, activation of frequent discharge of neurons occurred. In this situation, stimulation of the CA1 and CA3 areas was more accentuated than under conditions of normoxia. In the second phase (an altitude of 7.5-8 thousand meters), on the reduction of the impulse activity of neurons, stimulation of the CA1 and CA3 areas of the hippocampus induced untypical responses of these neurons.     

Comparison of direct influences of the perforant path on hippocampal CA1 and CA3 neurons in vitro

The efficiency of synapses of the perforant path located on terminals of apical dendrites of CA₁ and CA₃ neurons was investigated in sections of the guinea pig hippocampus in vitro. Neurons of both areas were shown to respond to stimulation of the perforant path by action potential generation. Responses of most CA₁ neurons appeared to repetitive stimulation with a frequency of up to 30–80/sec. Neurons in area CA₃ respond only to low-frequency stimulation (under 5/sec). Posttetanic potentiation of responses to stimulation of the perforant path was found in both areas of the hippocampus.Institute of Biophysics, Academy of Sciences of the USSR, Pushchino-on-Oka. Translated from Neirofiziologiya, Vol. 11, No. 4, pp. 303–310, July–August, 1979.     

Changes in inhibitory CA1 network in dual pathology model of epilepsy

The combination of two precipitating factors appears to be more and more recognized in patients with temporal lobe epilepsy. Using a two-hit rat model, with a neonatal freeze lesion mimicking a focal cortical malformation combined with hyperthermia-induced seizures mimicking febrile seizures, we have previously reported an increase of inhibition in CA1 pyramidal cells at P20. Here, we investigated the changes affecting excitatory and inhibitory drive onto CA1 interneurons to better define the changes in CA1 inhibitory networks and their paradoxical role in epileptogenesis, using electrophysiological recordings in CA1 hippocampus from rat pups (16–20 d old). We investigated interneurons in CA1 hippocampal area located in stratum oriens (Or) and at the border of strata lacunosum and moleculare (L-M). Our results revealed an increase of the excitatory drive to both types of interneurons with no change in the inhibitory drive. The mechanisms underlying the increase of excitatory synaptic currents (EPSCs) in both types of interneurons are different. In Or interneurons, the amplitude of spontaneous and miniature EPSCs increased, while their frequency was not affected suggesting changes at the post-synaptic level. In L-M interneurons, the frequency of spontaneous EPSCs increases, but the amplitude is not affected. Analyses of miniature EPSCs showed no changes in both their frequency and amplitude. We concluded that L-M interneurons increase in excitatory drive is due to a change in Shaffer collateral axon excitability. The changes described here in CA1 inhibitory network may actually contribute to the epileptogenicity observed in this dual pathology model by increasing pyramidal cell synchronization.     

Coincidence detection of place and temporal context in a network model of spiking hippocampal neurons

Recent advances in single-neuron biophysics have enhanced our understanding of information processing on the cellular level, but how the detailed properties of individual neurons give rise to large-scale behavior remains unclear. Here, we present a model of the hippocampal network based on observed biophysical properties of hippocampal and entorhinal cortical neurons. We assembled our model to simulate spatial alternation, a task that requires memory of the previous path through the environment for correct selection of the current path to a reward site. The convergence of inputs from entorhinal cortex and hippocampal region CA3 onto CA1 pyramidal cells make them potentially important for integrating information about place and temporal context on the network level. Our model shows how place and temporal context information might be combined in CA1 pyramidal neurons to give rise to splitter cells, which fire selectively based on a combination of place and temporal context. The model leads to a number of experimentally testable predictions that may lead to a better understanding of the biophysical basis of information processing in the hippocampus.     

Segmental cable evaluation of somatic transients in hippocampal neurons (CA1, CA3, and dentate).

This study describes a detailed cable model of neuronal structure, which can predict the effects of discrete transient inputs. Neurons in in vitro hippocampal slices (CA1 and CA3 pyramidal cells and dentate granule neurons; n = 4 each) were physiologically characterized and stained with horseradish peroxidase (HRP). The HRP morphology was approximated with numerous small segments. The cable model included both these segments and spatially dispersed dendritic spines. The transient response function at the soma of the segmental model was numerically derived, and charging responses to simulated current inputs were computed. These simulations were compared with the physiological charging responses from the somatic penetrations, using an analysis of the charging time constants (tau i) and intercepts. The time constant ratio (tau 0/tau 1) did not significantly differ between the observed and simulated responses. A second index of comparison was the equivalent cylinder electrotonic length (L), which was derived using only the tau i values and their intercepts. The L values also did not differ significantly between the observed and simulated transients and averaged 0.91 length constant. Thus, using criteria based only on analysis of charging responses, the segmental cable model recreated accurately the observed transients at the soma. The equivalent cylinder model (with a lumped soma) could also adequately simulate the observed somatic transients, using the same criteria. However, the hippocampal neurons (particularly the pyramidal cells) did not appear to satisfy the equivalent cylinder assumption anatomically. Thus, the analysis of somatic charging transients alone may not be sufficient to discriminate between the two models of hippocampal neurons. Anatomical evidence indicates that, particularly for discrete dendritic inputs, the detailed segmental model may be more appropriate than the equivalent cylinder model.     

Zinc modulation of glycine receptors in acutely isolated rat CA3 neurons

Glycine and GABA are the primary inhibitory neurotransmitters in the spinal cord and brain stem, with glycine exerting its physiological roles by activating strychnine-sensitive ionotropic receptors. Glycine receptors are also expressed in the brain, including the cortex and hippocampus, but their physiological roles and pharmacological properties are largely unknown. Here, we report the pharmacological properties of functional glycine receptors in acutely isolated rat CA3 neurons using conventional whole-cell patch clamp techniques. Both glycine and taurine, which are endogenous agonists of glycine receptors, elicited Cl(-) currents in a concentration-dependent manner. The glycine-induced current (I(Gly)) was inhibited by strychnine, picrotoxin or cyclothiazide in a concentration-dependent manner. At lower concentrations (0.01-1 microM), ICS-205,930 potentiated I(Gly), but at higher concentrations (>10 microM) it inhibited I(Gly). These pharmacological properties strongly suggest that CA3 neurons express functional strychnine-sensitive glycine receptors containing alpha2 subunits. Furthermore, at lower concentrations (1-30 microM), Zn(2+) potentiated I(Gly), but at higher concentrations (>100 microM) it inhibited I(Gly). Considering that Zn(2+) is synaptically co-released with glutamate from mossy fiber terminals that make excitatory synapses onto CA3 neurons, these results suggest that endogenous Zn(2+) modulation of these glycine receptors may have an important role in the excitability of CA3 neurons.