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Inhibitory axons are targeted in hippocampal cell culture by anti-Caspr2 autoantibodies associated with limbic encephalitis.

Pinatel D, Hivert B, Boucraut J, Saint-Martin M, Rogemond V, Zoupi L, Karagogeos D, Honnorat J, Faivre-Sarrailh C - Front Cell Neurosci (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Aix Marseille Université, CNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, CRN2M-UMR7286, Faculté de Médecine Nord Marseille, France.

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.

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Schematic representation of Caspr2 and Caspr2-Fc complementary distribution in hippocampal neurons. (A) Anti-Caspr2 autoantibodies target preferentially the axons of inhibitory neurons. (B) TAG-1 is required as a post-synaptic receptor of Caspr2.
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Figure 9: Schematic representation of Caspr2 and Caspr2-Fc complementary distribution in hippocampal neurons. (A) Anti-Caspr2 autoantibodies target preferentially the axons of inhibitory neurons. (B) TAG-1 is required as a post-synaptic receptor of Caspr2.

Mentions: In the present study, we analyzed autoantibodies against Caspr2 in a series of patients with LE. First, we determined that IgGs in the CSF of four out seven patients selectively react against the Discoïdin and LamininG1 N-terminal modules of Caspr2. Second, using live staining of hippocampal neurons in culture, we showed that autoimmunity to Caspr2 mainly targets hippocampal inhibitory interneurons (Figure 9A). Anti-Caspr2 IgGs label GAD65-positive pre-synaptic sites apposed to Gephyrin post-synaptic clusters. Functional assays indicated that LE autoantibodies may induce alteration of inhibitory synaptic contacts. Third, we used a Caspr2-Fc chimera to reveal Caspr2 receptors on hippocampal neurons. Caspr2 binding sites are distributed on the somato-dendritic compartment at post-synaptic sites. We showed that TAG-1 expression is essential for Caspr2-Fc binding on hippocampal neurons (Figure 9B). These results indicate that Caspr2 may participate as a cell recognition molecule in the dynamics of inhibitory networks. In addition, they point out to the immune targeting of inhibitory synapses as a critical clue for understanding the physiopathological role of Caspr2.


Inhibitory axons are targeted in hippocampal cell culture by anti-Caspr2 autoantibodies associated with limbic encephalitis.

Pinatel D, Hivert B, Boucraut J, Saint-Martin M, Rogemond V, Zoupi L, Karagogeos D, Honnorat J, Faivre-Sarrailh C - Front Cell Neurosci (2015)

Schematic representation of Caspr2 and Caspr2-Fc complementary distribution in hippocampal neurons. (A) Anti-Caspr2 autoantibodies target preferentially the axons of inhibitory neurons. (B) TAG-1 is required as a post-synaptic receptor of Caspr2.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496579&req=5

Figure 9: Schematic representation of Caspr2 and Caspr2-Fc complementary distribution in hippocampal neurons. (A) Anti-Caspr2 autoantibodies target preferentially the axons of inhibitory neurons. (B) TAG-1 is required as a post-synaptic receptor of Caspr2.
Mentions: In the present study, we analyzed autoantibodies against Caspr2 in a series of patients with LE. First, we determined that IgGs in the CSF of four out seven patients selectively react against the Discoïdin and LamininG1 N-terminal modules of Caspr2. Second, using live staining of hippocampal neurons in culture, we showed that autoimmunity to Caspr2 mainly targets hippocampal inhibitory interneurons (Figure 9A). Anti-Caspr2 IgGs label GAD65-positive pre-synaptic sites apposed to Gephyrin post-synaptic clusters. Functional assays indicated that LE autoantibodies may induce alteration of inhibitory synaptic contacts. Third, we used a Caspr2-Fc chimera to reveal Caspr2 receptors on hippocampal neurons. Caspr2 binding sites are distributed on the somato-dendritic compartment at post-synaptic sites. We showed that TAG-1 expression is essential for Caspr2-Fc binding on hippocampal neurons (Figure 9B). These results indicate that Caspr2 may participate as a cell recognition molecule in the dynamics of inhibitory networks. In addition, they point out to the immune targeting of inhibitory synapses as a critical clue for understanding the physiopathological role of Caspr2.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Aix Marseille Université, CNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, CRN2M-UMR7286, Faculté de Médecine Nord Marseille, France.

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.

No MeSH data available.


Related in: MedlinePlus