Pattern-Specific Synaptic Mechanisms in a Multifunctional Network. I. Effects of Alterations in Synapse Strength
ABSTRACT Many neuronal networks are multifunctional, producing different patterns of activity in different circumstances, but the mechanisms responsible for this reconfiguration are in many cases unresolved. The mammalian respiratory network is an example of such a system. Normal respiratory activity (eupnea) is periodically interrupted by distinct large-amplitude inspirations known as sighs. Both rhythms originate from a single multifunctional neural network, and both are preserved in the in vitro transverse medullary slice of mice. Here we show that the generation of fictive sighs were more sensitive than eupnea to reductions of excitatory synapse strength caused by either the P/Q-type (alpha1A-containing) calcium channel antagonist omega-agatoxin TK or the non-N-methyl-D-aspartate (NMDA) glutamate receptor antagonist 6-cyano-7-nitroquinoxalene-2,3-dione (CNQX). In contrast, the NMDA receptor antagonist MK-801, while also inhibiting eupnea, increased the occurrence of sighs. This suggests that among the glutamatergic synapses subserving eupneic rhythmogenesis, there is a specific subset-highly sensitive to agatoxin and insensitive to NMDA receptor blockade-that is essential for sighs. Blockade of N-type calcium channels with omega-conotoxin GVIA also had pattern-specific effects: eupneic activity was not affected, but sigh frequency was increased and postsigh apnea decreased. We hypothesize that N-type (alpha1B) calcium channels selectively coupled to calcium-activated potassium channels contribute to the generation of the postsigh apnea.
- SourceAvailable from: Yasumasa Okada
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- "For this purpose we used an AMPA/kainate-subtype glutamatergic receptor antagonist 6-cyano-7- nitroquinoxaline-2,3-dione (CNQX, 30 µM) but not an NMDA receptor blocker. This is because we considered that the synchronizing excitatory interactions would only require AMPA/kainate-subtype glutamatergic receptors as demonstrated by previous pharmacological experiments (Funk et al., 1993; Koshiya and Smith, 1999), although Lieske and Ramirez (2006a) argued that NMDA receptor is involved in respiratory rhythm generation. Voltage-imaging video signals taken at "
ABSTRACT: The preBötzinger complex (preBötC) of the ventrolateral medulla is the kernel for inspiratory rhythm generation. However, it is not fully understood how inspiratory neural activity is generated in the preBötC and propagates to other medullary regions. We analyzed the detailed anatomical connectivity to and from the preBötC and functional aspects of the inspiratory information propagation from the preBötC on the transverse plane of the medulla oblongata. Tract-tracing with immunohistochemistry in young adult rats demonstrated that neurokinin-1 receptor- and somatostatin-immunoreactive neurons in the preBötC, which could be involved in respiratory rhythmogenesis, are embedded in the plexus of axons originating in the contralateral preBötC. By voltage-imaging in rhythmically active slices of neonatal rats, we analyzed origination and propagation of inspiratory neural activity as depolarizing wave dynamics on the entire transverse plane as well as within the preBötC. Novel combination of pharmacological blockade of glutamatergic transmission and mathematical subtraction of the video images under blockade from the control images enabled to extract glutamatergic signal propagations. By ultra-high-speed voltage-imaging we first demonstrated the inter-preBötC conduction process of inspiratory action potentials. Intra-preBötC imaging with high spatiotemporal resolution during single spontaneous inspiratory cycle unveiled deterministic nonlinearities, i.e., chaos, in the population recruitment. Collectively, we comprehensively elucidated the anatomical pathways to and from the preBötC and dynamics of inspiratory neural information propagation: (1) From the preBötC in one side to the contralateral preBötC, which would synchronize the bilateral rhythmogenic kernels, (2) from the preBötC directly to the bilateral hypoglossal premotor and motor areas as well as to the nuclei tractus solitarius, and (3) from the hypoglossal premotor areas toward the hypoglossal motor nuclei. The coincidence of identified anatomical and functional connectivity between the preBötC and other regions in adult and neonatal rats, respectively, indicates that this fundamental connectivity is already well developed at the time of birth.Neuroscience 03/2014; 268. DOI:10.1016/j.neuroscience.2014.03.002 · 3.33 Impact Factor
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- "Loss of Ca v 2.1 reduced glutamatergic transmission within the preBötC. Our pharmacological experiments confirmed that Ca v 2.2 accounts for ~30% of excitatory synaptic transmission (Lieske and Ramirez, 2006). In KO slices, EPSP amplitudes were reduced, and further pharmacological blockade of Ca v 2.2 abolished EPSPs. "
ABSTRACT: P/Q-type voltage-gated calcium channels (Ca(v)2.1) play critical presynaptic and postsynaptic roles throughout the nervous system and have been implicated in a variety of neurological disorders. Here we report that mice with a genetic ablation of the Ca(v)2.1 pore-forming α(1A) subunit (α(1A)(-/-)) encoded by CACNA1a (Jun et al., 1999) suffer during postnatal development from increasing breathing disturbances that lead ultimately to death. Breathing abnormalities include decreased minute ventilation and a specific loss of sighs, which was associated with lung atelectasis. Similar respiratory alterations were preserved in the isolated in vitro brainstem slice preparation containing the pre-Bötzinger complex. The loss of Ca(v)2.1 was associated with an alteration in the functional dependency on N-type calcium channels (Ca(v)2.2). Blocking N-type calcium channels with conotoxin GVIA had only minor effects on respiratory activity in slices from control (CT) littermates, but abolished respiratory activity in all slices from α(1A)(-/-) mice. The amplitude of evoked EPSPs was smaller in inspiratory neurons from α(1A)(-/-) mice compared with CTs. Conotoxin GVIA abolished all EPSPs in inspiratory neurons from α(1A)(-/-) mice, while the EPSP amplitude was reduced by only 30% in CT mice. Moreover, neuromodulation was significantly altered as muscarine abolished respiratory network activity in α(1A)(-/-) mice but not in CT mice. We conclude that excitatory synaptic transmission dependent on N-type and P/Q-type calcium channels is required for stable breathing and sighing. In the absence of P/Q-type calcium channels, breathing, sighing, and neuromodulation are severely compromised, leading to early mortality.The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 02/2013; 33(8):3633-3645. DOI:10.1523/JNEUROSCI.6390-11.2013 · 6.75 Impact Factor
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- "The rhythmic activities characterizing sigh and eupneic activities seem to emerge by way of the differential activation of different synaptic and intrinsic membrane properties (Lieske and Ramirez 2006a, 2006b; Tryba et al. 2008). Generation of a sigh is critically dependent on P-type calcium currents and involves the activation of group III mGluR 8 receptors, while other metabotropic glutamate receptors are critical for the generation of eupneic activity (Lieske and Ramirez 2006a, 2006b). Intrinsic properties of membranes seem to be as critical as different activation of synaptic mechanisms in mediating the configurations of this network. "
ABSTRACT: Neuronal networks are highly plastic and reconfigure in a state-dependent manner. The plasticity at the network level emerges through multiple intrinsic and synaptic membrane properties that imbue neurons and their interactions with numerous nonlinear properties. These properties are continuously regulated by neuromodulators and homeostatic mechanisms that are critical to maintain not only network stability and also adapt networks in a short- and long-term manner to changes in behavioral, developmental, metabolic, and environmental conditions. This review provides concrete examples from neuronal networks in invertebrates and vertebrates, and illustrates that the concepts and rules that govern neuronal networks and behaviors are universal.Integrative and Comparative Biology 08/2011; 51(6):856-68. DOI:10.1093/icb/icr099 · 2.97 Impact Factor