Nucleus-specific abnormalities of GABAergic synaptic transmission in a genetic model of absence seizures

Human and experimental studies indicate that molecular genetic changes in GABA(A) receptors may underlie the expression of spike-and-waves discharges (SWDs) occurring during absence seizures. However, the full spectrum of the genetic defects underlying these seizures has only been partially elucidated, the expression and functional profiles of putative abnormal protein(s) within the thalamocortical network are undefined, and the pathophysiological mechanism(s) by which these proteins would lead to absence paroxysms are poorly understood. Here we investigated GABA(A) inhibitory postsynaptic currents (IPSCs) in key thalamocortical areas, i.e., the somatosensory cortex, ventrobasal thalamus (VB) and nucleus reticularis thalami (NRT), in preseizure genetic absence epilepsy rats from Strasbourg (GAERS), a well-established genetic model of typical absence seizures that shows no additional neurological abnormalities, and compared their properties to age-matched non-epileptic controls (NECs). Miniature GABA(A) IPSCs of VB and cortical layers II/III neurons were similar in GAERS and NEC, whereas in GAERS NRT neurons they had 25% larger amplitude, 40% faster decay. In addition, baclofen was significantly less effective in decreasing the frequency of NRT mIPSCs in GAERS than in NEC, whereas no difference was observed for cortical and VB mIPSCS between the two strains. Paired-pulse depression was 45% smaller in GAERS NRT, but not in VB, and was insensitive to GABA(B) antagonists. These results point to subtle, nucleus-specific, GABA(A) receptor abnormalities underlying SWDs of typical absence seizures rather than a full block of these receptors across the whole thalamocortical network, and their occurrence prior to seizure onset suggests that they might be of epileptogenic significance.     

Further study of the role of calcium in synaptic transmission

1. The effect of calcium on synaptic transmission has been studied by intracellular recording of pre- and post-synaptic potential changes in the stellate ganglion of the squid.2. For a given presynaptic ;input' (propagated spike, or local depolarizing pulse after tetrodotoxin treatment), the post-synaptic response increases with external calcium concentration [Ca](o) in a highly non-linear fashion, indicating that transmitter output varies with more than the second power of [Ca](o) over a certain concentration range.     

KCNQ/Kv7 channel regulation of hippocampal gamma-frequency firing in the absence of synaptic transmission

Synchronous neuronal firing can be induced in hippocampal slices in the absence of synaptic transmission by lowering extracellular Ca2+ and raising extracellular K+. However, the ionic mechanisms underlying this nonsynaptic synchronous firing are not well understood. In this study we have investigated the role of KCNQ/Kv7 channels in regulating this form of nonsynaptic bursting activity. Incubation of rat hippocampal slices in reduced (<0.2 mM) [Ca2+]o and increased (6.3 mM) [K+]o, blocked synaptic transmission, increased neuronal firing, and led to the development of spontaneous periodic nonsynaptic epileptiform activity. This activity was recorded extracellularly as large (4.7 +/- 1.9 mV) depolarizing envelopes with superimposed high-frequency synchronous population spikes. These intraburst population spikes initially occurred at a high frequency (about 120 Hz), which decayed throughout the burst stabilizing in the gamma-frequency band (30-80 Hz). Further increasing [K+]o resulted in an increase in the interburst frequency without altering the intraburst population spike frequency. Application of retigabine (10 microM), a Kv7 channel modulator, completely abolished the bursts, in an XE-991-sensitive manner. Furthermore, application of the Kv7 channel blockers, linopirdine (10 microM) or XE-991 (10 microM) alone, abolished the gamma frequency, but not the higher-frequency population spike firing observed during low Ca2+/high K+ bursts. These data suggest that Kv7 channels are likely to play a role in the regulation of synchronous population firing activity.     

Rhythmic neuronal discharge in the medulla and spinal cord of fetal rats in the absence of synaptic transmission

Spontaneous rhythmic neuronal activity is generated in the developing vertebrate nervous system. The patterned activity spreads diffusely throughout the fetal neuraxis. Here we demonstrate the ability of the fetal rat spinal cord and medulla to generate and transmit robust rhythmic patterns in the absence of synaptic activity. Regular rhythmic discharges were produced by fetal tissue bathed in low or zero [Ca(2+)](o) solution. The activity persisted in the presence of antagonists to neurotransmitter receptors that are known to mediate synaptic-mediated events associated with fetal rhythms. A combination of ventral root recordings and optical imaging using voltage-sensitive dyes demonstrated the extensive spread of rhythmic discharge in spinal cord and medullary neuronal populations of in vitro preparations. Whole cell recordings from medullary slices were performed to examine the ionic conductances and revealed the importance of persistent sodium conductances for generation of rhythmic activity in hypoglossal (XII) motoneurons. Rhythmic bursting in XII motoneurons persisted in the presence of gap junction blockers, although the amplitude of synchronized motor discharge recorded from nerve roots was diminished. We propose that nonsynaptically mediated conductances, potentially by extracellular ionic flux and/or ephaptic and electrotonic interactions mechanisms, act in concert with neurochemical transmission and gap junctions to promote the diffuse spread of rhythmic motor patterns in the developing nervous system.     

Firing properties of respiratory rhythm generating neurons in the absence of synaptic transmission in rat medulla in vitro

Summary It has previously been demonstrated that Pre-I neurons, localized in the rostral ventrolateral medulla, are important in the generation of the primary respiratory rhythm in brainstemspinal cord preparations from newborn rats. To investigate whether or not Pre-I neurons have endogenous pacemaker properties, we examined Pre-I neuron activity before and after chemical synaptic transmission was blocked by incubation in a low Ca²⁺ (0.2 mM), high Mg²⁺ (5 mM) solution (referred to here as low Ca). After incubation for about 30 min in low Ca, 28 (52%, type-1) out of 54 neurons tested in 27 preparations retained apparent rhythmic (phasic) activity after complete disappearance of C4 inspiratory activity. Sixteen neurons (30%, type-2) fired tonically and 10 (18%, type-3) were silent. We examined the effects of synaptic blockade on 14 inspiratory neurons in the RVL. The firing of all 14 neurons in 9 preparations disappeared concomitantly with the disappearance of C4 activity in low Ca. When the pH of the low Ca solution was lowered with a decrease in NaHCO₃ concentration from 7.4 to 7.1, the firing rate of the Pre-I neurons (type-1) increased from 12 to 18/min. In conclusion, the generator of respiratory rhythm in the newborn rat is probably a neuronal network with chemical synapses that functions mainly through the endogenous Pre-I pacemaker cells. Intrinsic chemoreception in the rhythm generator is probably important in frequency control of respiratory rhythm.     

The effect of electrical polarization of the motor nerve endings on the transmission through them of single impulses

Summary A frog nerve-muscle preparation was used to study the effects of depolarization and hyperpolarization of the transmission of single impulses at nerve endings. The efficacy of synaptic transmission was determined by the value of the end-plate potential led off intracellularly from the muscle fiber. Depolarization of the nerve endings produced a rapid reduction of up to 10–20% in the trans-synaptic action of the ending. Hyperpolarization of the endings caused the efficacy of trans-synaptic action to increase slowly for three minutes. In such cases the end-plate potential rose to 3 or 4 times the control level. These changes were observed only with a local polarization of the region of the nerve endings, and were absent when the preterminal branches of the nerve were polarized. (Presented by Active Member AMN SSSR V. V. Parin) Translated from Byulleten' éksperimental'noi Biologii i Meditsiny, Vol. 6, No. 11, pp. 11–14, November, 1963     

Chemical synaptic transmission in the cochlea

The last two decades have witnessed major progress in the understanding of cochlear mechanical functioning, and in the emergence of cochlear neurochemistry and neuropharmacology. Recent models describe active processes within the cochlea that amplify and sharpen the mechanical response to sound. Although it is widely accepted that outer hair cells (OHCs) contribute to these processes, the nature of the medial efferent influence on cochlear mechanics needs further clarification. Acetylcholine (ACh) is the major transmitter released onto OHCs during the stimulation of these efferents. The inhibitory influence of this system is mediated by post- and presynaptic nicontinic and muscarinic receptors and the role of other neuroactive substances [γ-aminobutyric acid (GABA), calcitonin gene-related peptide (CGRP), adenosine 5′-triphosphate (ATP) or nitric oxide (NO)] remains to be determined. The inner hair cells (IHCs) that transduce the mechanical displacements into neural activity, release glutamate on receptor-activated channels of AMPA, kainate, and NMDA types. This synapse is in turn controlled and/or regulated by the lateral efferents containing a cocktail of neuroactive substances (ACh, GABA, dopamine, enkephalins, dynorphin, CGRP). This glutamatergic nature of the IHCs is responsible for the acute destruction of the nerve endings and subsequently for neuronal death, damage usually described in various cochlear diseases (noise-induced hearing losses, neural presbycusis and certain forms of sudden deafness or peripheral tinnitus). These pathologies also include a regrowth of new dendritic processes by surviving neurons up to IHCs. Understanding the subtle molecular mechanisms which underly the control of neuronal excitability, synaptic plasticity and neuronal death in cochlear function and disease is a very important issue for the development of future therapies.     

激光诱发听觉系统神经冲动的研究进展

近年来利用激光诱发神经冲动逐渐成为研究的热点。本文归纳整理了近7年来激光在刺激听神经方面的主要研究进展,包括激光诱发耳蜗内听神经冲动的研究、激光参数和神经组织特性对激光诱发耳蜗听神经冲动的影响,并对激光诱发听神经冲动的安全性、多通道激光刺激、扩大激光刺激参数的范围等方面进行了展望。