Neuronal Dystroglycan regulates postnatal development of CCK/cannabinoid receptor-1 interneurons

Abstract

The development of functional neural circuits requires the precise formation of synaptic connections between diverse neuronal populations. The molecular pathways that allow GABAergic interneuron subtypes in the mammalian brain to recognize their postsynaptic partners remain largely unknown. The transmembrane glycoprotein Dystroglycan is localized to inhibitory synapses in pyramidal neurons, where it is required for the proper function of CCK+ interneurons. We show that deletion of Dystroglycan from pyramidal neurons selectively impairs CCK+ interneuron development during the first postnatal week. In the absence of postsynaptic Dystroglycan, presynaptic CCK+ interneurons fail to elaborate their axons and largely disappear from the cortex, hippocampus, amygdala, and olfactory bulb. Bax deletion did not rescue CCK+ interneurons, suggesting that they are not eliminated by canonical apoptosis in Dystroglycan mutants. Rather, we observed an increase in CCK+ interneuron innervation of the striatum, suggesting that the remaining CCK+ interneurons re-directed their axons to neighboring areas where Dystroglycan expression remained intact. Together these findings identify Dystroglycan as a critical regulator of CCK+ interneuron development.

An adhesion signaling axis involving Dystroglycan, β1-Integrin and Cas adaptor proteins regulates the establishment of the cortical glial scaffold

“…4A ). Interestingly, these phenotypes are also likely RGC-autonomous, as deletion of DG in postmitotic neurons using NexCre does not disrupt cortical lamination (Satz et al, 2010; Miller & Wright, 2021). In addition to supporting the reproducibility of previous reports, this provides definitive evidence that the Emx1Cre;CasTcKO cortical organization phenocopies multiple aspects of the defects observed when DG is conditionally ablated in early cortical progenitors.…”

The many roles of dystroglycan in nervous system development and function

“…Defining which binding events are important at any one time or place is complicated, as loss of DAG1 or its defective glycosylation affects all of these interactions. For example, Dag1 in the spinal cord floor plate governs axon guidance by simultaneously binding ECM proteins such as laminin to regulate basal lamina integrity, coordinating the distribution of secreted Slit proteins, and binding the axon guidance receptor Celsr3/Adgrc3 in trans 35,76 . While Dag1 can bind presynaptic Neurexins, this is unlikely to be the sole extracellular binding partner that mediates Dag1 function at inhibitory synapses 32 .…”

“…27,[64][65][66]70,74 In contrast, when deletion of DAG1 is restricted to newly born pyramidal neurons using NEX Cre , cortical migration is normal. 27,75,76 This demonstrates that the neuronal migration phenotype in DAG1 mutants is non-cell autonomous, with neuroepithelial cells playing the primary role as a scaffold to support proper neuronal migration. Similarly, in the cerebellum, Nestin Cre and hGFAP Cre conditional mutants show the abovedescribed granule cell migration phenotype while L7 Cre (Purkinje neurons) and mAlpha6 Cre (granule cells) conditional knockouts exhibit normal Purkinje neuron and granule cell development.…”

“…34,35 Since the initial discovery of a role for Dag1 in axon guidance in the spinal cord, additional work has identified the importance of Dag1 for axon guidance in the internal capsule, lateral olfactory tract, anterior commissure, and optic chiasm, supporting a conserved role for Dag1 in axon guidance across multiple systems. 35,[74][75][76]85 The internal capsule is comprised of descending corticothalamic axons (CTAs) and ascending thalamocortical axons (TCAs). A third population of "corridor cells" acts as an intermediate target to facilitate the guidance of CTAs and TCAs as they navigate through the ventral forebrain.…”

“…In the hippocampus, DAG1 is expressed by pyramidal neurons in CA1–CA3 and is required for the perisomatic innervation of these neurons by presynaptic CCK+ basket interneurons. Postsynaptic deletion of DAG1 from pyramidal cells ( NEX Cre ) results in the total loss of CCK+ basket interneuron axons as determined by immunostaining with markers for the specific population (VGluT3, CB 1 R), whereas the PV+ population of basket interneurons remains unaffected 75,76 . Interestingly, a distinct phenotype is observed when DAG1 is deleted from neurons and glia ( Emx1 Cre , Nestin Cre ).…”