Dataset Information

The Auxiliary Calcium Channel Subunit ?2?4 Is Required for Axonal Elaboration, Synaptic Transmission, and Wiring of Rod Photoreceptors.

ABSTRACT: Neural circuit wiring relies on selective synapse formation whereby a presynaptic release apparatus is matched with its cognate postsynaptic machinery. At metabotropic synapses, the molecular mechanisms underlying this process are poorly understood. In the mammalian retina, rod photoreceptors form selective contacts with rod ON-bipolar cells by aligning the presynaptic voltage-gated Ca2+ channel directing glutamate release (CaV1.4) with postsynaptic mGluR6 receptors. We show this coordination requires an extracellular protein, ?2?4, which complexes with CaV1.4 and the rod synaptogenic mediator, ELFN1, for trans-synaptic alignment with mGluR6. Eliminating ?2?4 in mice abolishes rod synaptogenesis and synaptic transmission to rod ON-bipolar cells, and disrupts postsynaptic mGluR6 clustering. We further find that in rods, ?2?4 is crucial for organizing synaptic ribbons and setting CaV1.4 voltage sensitivity. In cones, ?2?4 is essential for CaV1.4 function, but is not required for ribbon organization, synaptogenesis, or synaptic transmission. These findings offer insights into retinal pathologies associated with ?2?4 dysfunction.

SUBMITTER: Wang Y

PROVIDER: S-EPMC5364038 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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The Auxiliary Calcium Channel Subunit α2δ4 Is Required for Axonal Elaboration, Synaptic Transmission, and Wiring of Rod Photoreceptors.

Wang Yuchen Y Fehlhaber Katherine E KE Sarria Ignacio I Cao Yan Y Ingram Norianne T NT Guerrero-Given Debbie D Throesch Ben B Baldwin Kristin K Kamasawa Naomi N Ohtsuka Toshihisa T Sampath Alapakkam P AP Martemyanov Kirill A KA

Neuron 20170302 6

Neural circuit wiring relies on selective synapse formation whereby a presynaptic release apparatus is matched with its cognate postsynaptic machinery. At metabotropic synapses, the molecular mechanisms underlying this process are poorly understood. In the mammalian retina, rod photoreceptors form selective contacts with rod ON-bipolar cells by aligning the presynaptic voltage-gated Ca<sup>2+</sup> channel directing glutamate release (Ca<sub>V</sub>1.4) with postsynaptic mGluR6 receptors. We sho ...[more]

PMID: 28262416

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Project description:Presynaptic α2δ subunits of voltage-gated calcium channels regulate channel abundance and are involved in glutamatergic synapse formation. However, little is known about the specific functions of the individual α2δ isoforms and their role in GABAergic synapses. Using primary neuronal cultures of embryonic mice of both sexes, we here report that presynaptic overexpression of α2δ-2 in GABAergic synapses strongly increases clustering of postsynaptic GABAARs. Strikingly, presynaptic α2δ-2 exerts the same effect in glutamatergic synapses, leading to a mismatched localization of GABAARs. This mismatching is caused by an aberrant wiring of glutamatergic presynaptic boutons with GABAergic postsynaptic positions. The trans-synaptic effect of α2δ-2 is independent of the prototypical cell-adhesion molecules α-neurexins (α-Nrxns); however, α-Nrxns together with α2δ-2 can modulate postsynaptic GABAAR abundance. Finally, exclusion of the alternatively spliced exon 23 of α2δ-2 is essential for the trans-synaptic mechanism. The novel function of α2δ-2 identified here may explain how abnormal α2δ subunit expression can cause excitatory-inhibitory imbalance often associated with neuropsychiatric disorders.SIGNIFICANCE STATEMENT Voltage-gated calcium channels regulate important neuronal functions such as synaptic transmission. α2δ subunits modulate calcium channels and are emerging as regulators of brain connectivity. However, little is known about how individual α2δ subunits contribute to synapse specificity. Here, we show that presynaptic expression of a single α2δ variant can modulate synaptic connectivity and the localization of inhibitory postsynaptic receptors. Our findings provide basic insights into the development of specific synaptic connections between nerve cells and contribute to our understanding of normal nerve cell functions. Furthermore, the identified mechanism may explain how an altered expression of calcium channel subunits can result in aberrant neuronal wiring often associated with neuropsychiatric disorders such as autism or schizophrenia.

Project description:PurposeMutations in the CACNA1F gene encoding the L-type calcium channel pore-forming Ca(v)1.4 (alpha1F) subunit in humans result in an incomplete form of congenital stationary night blindness (CSNB2) with residual photoreceptor function. It has been postulated that this residual function, at least in part, may be mediated by another L-type calcium channel subunit, Ca(v)1.3 (alpha1D), expressed within cone photoreceptors. However, the expression of the calcium channel Ca(v)1.3 (alpha1D) subunit within photoreceptors remains debatable due to discrepancies among the immunohistochemical studies reported in the literature. In order to get around the innate complications of utilizing unproven antibodies and to shed light on this discussion, we investigated the mRNA expression profile for the Ca(v)1.3 (alpha1D) subunit in the mouse retina.MethodsIn situ hybridization was performed on wild type mouse retinal sections with two independent sets of digoxigenin-11-UTP-labeled Ca(v)1.3 (alpha1D)-specific sense and antisense cRNA probes. The two probe sets employed correspond to two distinct regions of the Ca(v)1.3 (alpha1D) subunit mRNA, each encoding a different fragment of the Ca(v)1.3 (alpha1D) polypeptide. In situ hybridization of wild type mouse brain sections with these same probes was performed as an additional control for specificity.ResultsAbundant L-type calcium channel Ca(v)1.3 (alpha1D) subunit mRNA expression was confirmed in most cells of the outer nuclear layer using two independent Ca(v)1.3 (alpha1D)-specific antisense cRNA probes, confirming expression in rod photoreceptors. Ca(v)1.3 (alpha1D) mRNA expression was also observed within most cells of the inner nuclear layer and ganglion cell layers using these same antisense cRNA probes. No labeling of tissue was observed using either sense cRNA probe. In situ detection of concentrated Ca(v)1.3 (alpha1D) mRNA expression within the hippocampus and Purkinje and granule cells of the cerebellum of wild type mouse brain with these same probes confirmed specificity of the probes.ConclusionsOur finding of expression of the L-type calcium channel Ca(v)1.3 (alpha1D) subunit mRNA in rods substantiates the possibility that this pore-forming subunit may be a competent component of channels mediating the residual photoreceptor responses observed in mutant mice lacking functional Ca(v)1.4 (alpha1F) subunits and in humans with CSNB2. Furthermore, the combined observations of abundant expression of Ca(v)1.3 (alpha1D) mRNA in wild type rods and the large reduction in the transmission of photoreceptor responses in mice lacking Ca(v)1.4 (alpha1F) raises the possibility that Ca(v)1.3 (alpha1D) protein expression levels, localization, or functioning might be concomitantly altered by disruption of the Ca(v)1.4 (alpha1F) subunit in rods. To date, no studies of Ca(v)1.3 (alpha1D) mRNA nor protein expression levels or localization in cacna1f mutant mice or humans with CSNB2 have been published. Our findings warrant such studies to address the abovementioned possibilities. Finally, the observation of Ca(v)1.3 (alpha1D) mRNA expression in multiple retinal cell types suggests the potential for a broader role for this L-type calcium channel subunit in overall functioning of the normal retina than previously appreciated. We therefore suggest that lesions in either the gene encoding the L-type calcium channel Ca(v)1.3 (alpha1D) subunit or other molecules that interact with and regulate it may underlie one or more retinopathies with currently unidentified molecular etiologies.

Dataset Information

The Auxiliary Calcium Channel Subunit ?2?4 Is Required for Axonal Elaboration, Synaptic Transmission, and Wiring of Rod Photoreceptors.

Publications

The Auxiliary Calcium Channel Subunit α2δ4 Is Required for Axonal Elaboration, Synaptic Transmission, and Wiring of Rod Photoreceptors.

Similar Datasets

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