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The integration of somatosensory information is generally assumed to be a function of the central nervous system (CNS). Here we describe fully functional GABAergic communication within rodent peripheral sensory ganglia and show that it can modulate transmission of pain-related signals from the peripheral sensory nerves to the CNS. We found that sensory neurons express major proteins necessary for GABA synthesis and release and that sensory neurons released GABA in response to depolarization. In vivo focal infusion of GABA or GABA reuptake inhibitor to sensory ganglia dramatically reduced acute peripherally induced nociception and alleviated neuropathic and inflammatory pain. In addition, focal application of GABA receptor antagonists to sensory ganglia triggered or exacerbated peripherally induced nociception. We also demonstrated that chemogenetic or optogenetic depolarization of GABAergic dorsal root ganglion neurons in vivo reduced acute and chronic peripherally induced nociception. Mechanistically, GABA depolarized the majority of sensory neuron somata, yet produced a net inhibitory effect on the nociceptive transmission due to the filtering effect at nociceptive fiber T-junctions. Our findings indicate that peripheral somatosensory ganglia represent a hitherto underappreciated site of somatosensory signal integration and offer a potential target for therapeutic intervention.

Pyramidal neurons in the CA3 region of the hippocampal formation integrate synaptic information arriving in the dendrites within discrete laminar regions. At potentials near or below the resting potential integration of synaptic signals is most affected by the passive properties of the cell and hyperpolarization-activated currents (I(h)). Here we focused specifically on a subset of neurons within the CA3b subregion of the rat hippocampus in order to better understand their membrane response within subthreshold voltage ranges. Using a combined experimental and computational approach we found that the passive properties of these neurons varied up to fivefold between cells. Likewise, there was a large variance in the expression of I(h) channels. However, the contribution of I(h) was minimal at resting potentials endowing the membrane with an apparent linear response to somatic current injection within +/-10 mV. Unlike in CA1 pyramidal neurons, however, I(h) activation was not potentiated in an activity-dependent manner. Computer modeling, based on a combination of voltage- and current-clamp data, suggested that an increasing density of these channels with distance from the soma, compared with a uniform distribution, would have no significant effect on the general properties of the cell because of their relatively lower expression. Nonetheless, temporal summation of excitatory inputs was affected by the presence of I(h) in the dendrites in a frequency- and distance-dependent fashion.

Communication between the dentate gyrus (DG) and area CA3 of the hippocampus proper is transmitted via axons of granule cells--the mossy fiber (MF) pathway. In this review we discuss and compare the properties of transmitter release from the MFs onto pyramidal neurons and interneurons. An examination of the anatomical connectivity from DG to CA3 reveals a surprising interplay between excitation and inhibition for this circuit. In this respect it is particularly relevant that the major targets of the MFs are interneurons and that the consequence of MF input into CA3 may be inhibitory or excitatory, conditionally dependent on the frequency of input and modulatory regulation. This is further complicated by the properties of transmitter release from the MFs where a large number of co-localized transmitters, including GABAergic inhibitory transmitter release, and the effects of presynaptic modulation finely tune transmitter release. A picture emerges that extends beyond the hypothesis that the MFs are simply "detonators" of CA3 pyramidal neurons; the properties of synaptic information flow from the DG have more subtle and complex influences on the CA3 network.

1. We investigated the effects of metabotropic glutamate (mGlu) receptor activation on intracellular Ca2+ concentration ([Ca2+]i) in the soma and dendrites of hippocampal CA1 pyramidal neurons. Changes in [Ca2+]i were measured using confocal imaging simultaneously with whole-cell recording techniques. Differences in [Ca2+]i were visualized as changes in the fluorescence of the Ca(2+)-sensitive dye Fluo-3. 2. Brief application of the specific mGlu receptor agonist (1S,3R)-ACPD to either the apical or basal dendrites produced initially localized increases in [Ca2+]i that subsequently propagated as waves throughout much of the neuron. These Ca2+ waves, which propagated at approximately 40 microns/s, were shown not to reflect intracellular Ca2+ diffusion or extracellular diffusion of ACPD and were always accompanied by small outward membrane currents. 3. Repetitive application of ACPD failed to trigger further Ca2+ release. We found that a threshold level of voltage-gated Ca2+ entry during trains of action potentials was needed to prime further mGlu-stimulated Ca2+ release. In contrast, the passage of time alone did not cause the mGlu-release system to reactivate--restoration of ACPD-stimulated Ca2+ release. The spike-mediated Ca2+ signal was unaffected by mGlu-stimulated depletion of intracellular stores. 4. These experiments demonstrate that specific mGlu receptor activation can mobilize Ca2+ in dendrites of CA1 neurons and trigger waves of Ca(2+)-induced Ca(2+)-release throughout the cell. A use-dependent relationship between voltage-gated Ca2+ entry during trains of action potentials and mGlu-stimulated Ca2+ release is suggested.

The dendritic trees of neurons are structurally and functionally complex integrative units receiving thousands of synaptic inputs that have excitatory and inhibitory, fast and slow, and electrical and biochemical effects. The pattern of activation of these synaptic inputs determines if the neuron will fire an action potential at any given point in time and how it will respond to similar inputs in the future. Two critical factors affect the integrative function of dendrites: the distribution of voltage-gated ion channels in the dendritic tree and the passive electrical properties, or 'electrotonic structure', upon which these active channels are superimposed. The authors review recent data from patch-clamp recordings that provide new estimates of the passive membrane properties of hippocampal neurons, and show, with examples, how these properties affect the shaping and attenuation of synaptic potentials as they propagate in the dendrites, as well as how they affect the measurement of current from synapses located in the dendrites. Voltage-gated channels might influence the measurement of 'passive' membrane properties and, reciprocally, passive membrane properties might affect the activation of voltage-gated channels in dendrites.

1. High-speed fluorescence imaging was used to measure intracellular Ca2+ concentration ([Ca2+]i) changes in hippocampal neurons injected with the Ca(2+)-sensitive indicator fura-2 during intrasomatic and synaptic stimulation. The results of these experiments were used to construct a biophysical model of [Ca2+]i dynamics in hippocampal neurons. 2. A compartmental model of a pyramidal neuron was constructed incorporating published passive membrane properties of these cells, three types of voltage-gated Ca2+ channels characterized from adult hippocampal neurons, voltage-gated Na+ and K+ currents, and mechanisms for Ca2+ buffering and extrusion. 3. In hippocampal pyramidal neurons imaging of Na+ entry during electrical activity suggests that Na+ channels, at least in sufficient density to sustain action potentials, are localized in the soma and the proximal part of the apical dendritic tree. The model, which incorporates this distribution, demonstrates that action potentials attenuate steeply in passive distal dendritic compartments or distal dendritic compartments containing Ca2+ and K+ channels. This attenuation was affected by intracellular resistivity but not membrane resistivity. 4. Consistent with fluorescence imaging experiments, a non-uniform distribution of Ca2+ accumulation was generated by Ca2+ entry through voltage-gated Ca2+ channels opened by decrementally propagating Na+ action potentials. Consequently, the largest increases in [C2+]i were produced in the proximal dendrites. Distal voltage-gated Ca2+ currents were activated by broad, almost isopotential action potentials produced by reducing the overall density of K+ channels. 5. Simulations of subthreshold synaptic stimulation produced dendritic Ca2+ entry by the activation of voltage-gated Ca2+ channels. In the model these Ca2+ signals were localized near the site of synaptic input because of the attenuation of synaptic potentials with distance from the site of origin and the steep voltage-dependence of Ca2+ channel activation. 6. These simulations support the hypotheses generated from experimental evidence regarding the differential distribution of voltage-gated Ca2+ and Na+ channels in hippocampal neurons and the resulting voltage-gated Ca2+ accumulation from action and synaptic potentials.

1. The voltage- and space-clamp errors associated with the use of a somatic electrode to measure current from dendritic synapses are evaluated using both equivalent-cylinder and morphologically realistic models of neuronal dendritic trees. 2. As a first step toward understanding the properties of synaptic current distortion under voltage-clamp conditions, the attenuation of step and sinusoidal voltage changes are evaluated in equivalent cylinder models. Demonstration of the frequency-dependent attenuation of voltage in the cable is then used as a framework for understanding the distortion of synaptic currents generated at sites remote from the somatic recording electrode and measured in the voltage-clamp recording configuration. 3. Increases in specific membrane resistivity (Rm) are shown to reduce steady-state voltage attenuation, while producing only minimal reduction in attenuation of transient voltage changes. Experimental manipulations that increase Rm therefore improve the accuracy of estimates of reversal potential for electrotonically remote synapses, but do not significantly reduce the attenuation of peak current. In addition, increases in Rm have the effect of slowing the kinetics of poorly clamped synaptic currents. 4. The effects of the magnitude of the synaptic conductance and its kinetics on the measured synaptic currents are also examined and discussed. The error in estimating parameters from measured synaptic currents is greatest for synapses with fast kinetics and large conductances. 5. A morphologically realistic model of a CA3 pyramidal neuron is used to demonstrate the generality of the conclusions derived from equivalent cylinder models. The realistic model is also used to fit synaptic currents generated by stimulation of mossy fiber (MF) and commissural/associational (C/A) inputs to CA3 neurons and to estimate the amount of distortion of these measured currents. 6. Anatomic data from the CA3 pyramidal neuron model are used to construct a simplified two-cylinder CA3 model. This model is used to estimate the electrotonic distances of MF synapses (which are located proximal to the soma) and perforant path (PP) synapses (which are located at the distal ends of the apical dendrites) and the distortion of synaptic current parameters measured for these synapses. 7. Results from the equivalent-cylinder models, the morphological CA3 model, and the simplified CA3 model all indicate that the amount of distortion of synaptic currents increases steeply as a function of distance from the soma. MF synapses close to the soma are likely to be subject only to small space-clamp errors, whereas MF synapses farther from the soma are likely to be substantially attenuated.(ABSTRACT TRUNCATED AT 400 WORDS)