Journal of neurophysiology
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The ionic mechanisms that contribute to general anesthetic actions have not been elucidated, although increasing evidence has pointed to roles for subthreshold ion channels, such as the HCN channels underlying the neuronal hyperpolarization-activated cationic current (Ih). Here, we used conventional HCN1 knockout mice to test directly the contributions of specific HCN subunits to effects of isoflurane, an inhalational anesthetic, on membrane and integrative properties of motor and cortical pyramidal neurons in vitro. Compared with wild-type mice, residual Ih from knockout animals was smaller in amplitude and presented with HCN2-like properties. ⋯ Accordingly, anesthetic-induced EPSP summation was not observed in cortical cells from HCN1 knockout mice. In wild-type mice, the enhanced synaptic summation observed with low concentrations of isoflurane contributed to a net increase in cortical neuron excitability. In summary, HCN channel subunits account for distinct anesthetic effects on neuronal membrane properties and synaptic integration; inhibition of HCN1 in cortical neurons may contribute to the synaptically mediated slow-wave cortical synchronization that accompanies anesthetic-induced hypnosis.
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TRPV1 receptors are activated and/or modulated by noxious heat, capsaicin, protons and other endogenous agents released following tissue injury. There is a growing appreciation that this molecular integrator may also have a role in mechanosensation. To further understand this role, we investigated the systemic and site-specific effects of a selective TRPV1 receptor antagonist, A-889425, on low-intensity mechanical stimulation in inflamed rats. ⋯ Local injection experiments indicated that this effect of A-889425 on spontaneous firing was mainly mediated via TRPV1 receptors in the spinal cord. Thus the current data demonstrate that TRPV1 receptors have an enhanced role after an inflammatory injury, impacting both low-intensity mechanotransmission and possibly spontaneous pain. Furthermore this study delineates the differential contribution of central and peripheral TRPV1 receptors to affect spontaneous or mechanically evoked firing of WDR neurons.
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To explore the effects of acoustic and behavioral context on neuronal responses in the core of auditory cortex (fields A1 and R), two monkeys were trained on a go/no-go discrimination task in which they learned to respond selectively to a four-note target (S+) melody and withhold response to a variety of other nontarget (S-) sounds. We analyzed evoked activity from 683 units in A1/R of the trained monkeys during task performance and from 125 units in A1/R of two naive monkeys. We characterized two broad classes of neural activity that were modulated by task performance. ⋯ Class I responses may help encode a long-term representation of the behaviorally salient target melody. Class II activity may reflect a variety of nonacoustic influences, such as attention, reward expectancy, somatosensory inputs, and/or motor set and may help link auditory perception and behavioral response. Both types of neuronal activity are likely to contribute to the performance of the auditory task.
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In addition to its effects on neuronal survival and differentiation, brain-derived neurotrophic factor (BDNF) plays an important role in modulating synaptic transmission and plasticity in many brain areas, most notably the neocortex and hippocampus. These effects may underlie a role for BDNF in learning and memory as well as developmental plasticity. Consistent with localization of the tropomyosin-related kinase B receptor to both sides of the synapse, BDNF appears to have pre- and postsynaptic effects, but the underlying cellular mechanisms are unclear and it is not known whether pre- and postsynaptic modulations by BDNF occur simultaneously. ⋯ Surprisingly, the effect on frequency was also NMDA receptor dependent, but required activation of presynaptic, not postsynaptic, NMDA receptors. BDNF also enhanced action potential-dependent glutamate release via presynaptic NMDA receptors, an effect that was unmasked when voltage-gated calcium channels were partially inhibited. Our results indicate that BDNF acutely modulates presynaptic release and postsynaptic responsiveness through simultaneous effects on pre- and postsynaptic NMDA receptors.
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The importance of glial cells in the generation and maintenance of neuropathic pain is becoming widely accepted. We examined the role of glial-specific gap junctions in nociception in the rat trigeminal ganglion in nerve-injured and -uninjured states. The connexin 43 (Cx43) gap-junction subunit was found to be confined to the satellite glial cells (SGCs) that tightly envelop primary sensory neurons in the trigeminal ganglion and we therefore used Cx43 RNA interference (RNAi) to alter gap-junction function in SGCs. ⋯ Reducing Cx43 expression using RNAi in CCI rats reduced painlike behavior, whereas in non-CCI rats, reducing Cx43 expression increased painlike behavior. The degree of painlike behavior in CCI rats and intact, Cx43-silenced rats was similar. Our results support previous suggestions that increases in glial gap junctions after nerve injury increases nociceptive behavior but paradoxically the reduction of gap junctions in normal ganglia also increases nociceptive behavior, possibly a reflection of the multiple functions performed by glia.