Inda MC, DeFelipe J, Munoz A. Voltage-gated ion channels in the axon initial segment of human cortical pyramidal cells and their relationship with chandelier cells. Proc Natl Acad Sci USA 103: 2920-2925

Departamento de Biología Celular, Universidad Complutense de Madrid, Jose Antonio Novais 2, 28040 Madrid, Spain.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 03/2006; 103(8):2920-5. DOI: 10.1073/pnas.0511197103
Source: PubMed


The axon initial segment (AIS) of pyramidal cells is a critical region for the generation of action potentials and for the control of pyramidal cell activity. Here we show that Na+ and K+ voltage-gated channels, together with other molecules involved in the localization of ion channels, are distributed asymmetrically in the AIS of pyramidal cells situated in the human temporal neocortex. There is a high density of Na+ channels distributed along the length of the AIS together with the associated proteins spectrin betaIV and ankyrin G. In contrast, Kv1.2 channels are associated with the adhesion molecule Caspr2, and they are mostly localized to the distal region of the AIS. In general, the distal region of the AIS is targeted by the GABAergic axon terminals of chandelier cells, whereas the proximal region is innervated, mostly by other types of GABAergic interneurons. We suggest that this molecular segregation and the consequent regional specialization of the GABAergic input to the AIS of pyramidal cells may have important functional implications for the control of pyramidal cell activity.

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Available from: Javier Defelipe, Oct 05, 2014
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    • "Caspr2 also co-localizes with the Kv1.1/Kv1.2 channels at the axon initial segment and may regulate axonal excitability at this site (Inda et al., 2006; Ogawa et al., 2008). Apart from its well-known function in Kv1 channel clustering at juxtaparanodes, Caspr2 may also act as a cell recognition molecule during development and synaptic network formation. "
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    ABSTRACT: Contactin-associated protein-like 2 (Caspr2), also known as CNTNAP2, is a cell adhesion molecule that clusters voltage-gated potassium channels (Kv1.1/1.2) at the juxtaparanodes of myelinated axons and may regulate axonal excitability. As a component of the Kv1 complex, Caspr2 has been identified as a target in neuromyotonia and Morvan syndrome, but also in some cases of autoimmune limbic encephalitis (LE). How anti-Caspr2 autoimmunity is linked with the central neurological symptoms is still elusive. In the present study, using anti-Caspr2 antibodies from seven patients affected by pure LE, we determined that IgGs in the cerebrospinal fluid of four out seven patients were selectively directed against the N-terminal Discoïdin and LamininG1 modules of Caspr2. Using live immunolabeling of cultured hippocampal neurons, we determined that serum IgGs in all patients strongly targeted inhibitory interneurons. Caspr2 was highly detected on GAD65-positive axons that are surrounding the cell bodies and at the VGAT-positive inhibitory presynaptic contacts. Functional assays indicated that LE autoantibodies may induce alteration of Gephyrin clusters at inhibitory synaptic contacts. Next, we generated a Caspr2-Fc chimera to reveal Caspr2 receptors on hippocampal neurons localized at the somato-dendritic compartment and post-synapse. Caspr2-Fc binding was strongly increased on TAG-1-transfected neurons and conversely, Caspr2-Fc did not bind hippocampal neurons from TAG-1-deficient mice. Our data indicate that Caspr2 may participate as a cell recognition molecule in the dynamics of inhibitory networks. This study provides new insight into the potential pathogenic effect of anti-Caspr2 autoantibodies in central hyperexcitability that may be related with perturbation of inhibitory interneuron activity.
    Frontiers in Cellular Neuroscience 07/2015; 9:265. DOI:10.3389/fncel.2015.00265 · 4.29 Impact Factor
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    • "lusive to TTL5 neurons ( Shu et al . , 2007 ) and could be attributed to axonal AP initiation , owing in part to the high density of Na + channels housed in the AIS ( Inda et al . , 2006 ; McCormick et al . , 2007 ) . The structural evidence for a high Na + channel density in the AIS of cortical pyramidal neurons is both plentiful and conclusive ( Inda et al . , 2006 ; Kole et al . , 2008 ; Lörincz and Nusser , 2010 ) . However , what functional relevance does this high density confer ? Although it is tempting to subscribe to the interpretation that a high Na + channel density renders a low threshold in the AIS to facilitate AP initiation , the"
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    ABSTRACT: The thick-tufted layer 5 (TTL5) pyramidal neuron is one of the most extensively studied neuron types in the mammalian neocortex and has become a benchmark for understanding information processing in excitatory neurons. By virtue of having the widest local axonal and dendritic arborization, the TTL5 neuron encompasses various local neocortical neurons and thereby defines the dimensions of neocortical microcircuitry. The TTL5 neuron integrates input across all neocortical layers and is the principal output pathway funneling information flow to subcortical structures. Several studies over the past decades have investigated the anatomy, physiology, synaptology, and pathophysiology of the TTL5 neuron. This review summarizes key discoveries and identifies potential avenues of research to facilitate an integrated and unifying understanding on the role of a central neuron in the neocortex.
    Frontiers in Cellular Neuroscience 06/2015; 9:233. DOI:10.3389/fncel.2015.00233 · 4.29 Impact Factor
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    • "In the human cortex, chandelier cells selectively target the distal AIS regions where K + channel subtype K V 1.2 accumulates, suggesting important roles of chandelier cells in controlling the activity of PCs (Inda et al., 2006). In this study, we further revealed "
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    ABSTRACT: Studies in rodents revealed that selective accumulation of Na(+) channel subtypes at the axon initial segment (AIS) determines action potential (AP) initiation and backpropagation in cortical pyramidal cells (PCs); however, in human cortex, the molecular identity of Na(+) channels distributed at PC axons, including the AIS and the nodes of Ranvier, remains unclear. We performed immunostaining experiments in human cortical tissues removed surgically to cure brain diseases. We found strong immunosignals of Na(+) channels and two channel subtypes, NaV1.2 and NaV1.6, at the AIS of human cortical PCs. Although both channel subtypes were expressed along the entire AIS, the peak immunosignals of NaV1.2 and NaV1.6 were found at proximal and distal AIS regions, respectively. Surprisingly, in addition to the presence of NaV1.6 at the nodes of Ranvier, NaV1.2 was also found in a subpopulation of nodes in the adult human cortex, different from the absence of NaV1.2 in myelinated axons in rodents. NaV1.1 immunosignals were not detected at either the AIS or the nodes of Ranvier of PCs; however, they were expressed at interneuron axons with different distribution patterns. Further experiments revealed that parvalbumin-positive GABAergic axon cartridges selectively innervated distal AIS regions with relatively high immunosignals of NaV1.6 but not the proximal NaV1.2-enriched compartments, suggesting an important role of axo-axonic cells in regulating AP initiation in human PCs. Together, our results show that both NaV1.2 and NaV1.6 (but not NaV1.1) channel subtypes are expressed at the AIS and the nodes of Ranvier in adult human cortical PCs, suggesting that these channel subtypes control neuronal excitability and signal conduction in PC axons.
    Frontiers in Cellular Neuroscience 09/2014; 8:297. DOI:10.3389/fncel.2014.00297 · 4.29 Impact Factor
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