Neuregulin repellent signaling via ErbB4 restricts GABAergic interneurons to migratory paths from ganglionic eminence to cortical destinations

Abstract

BackgroundCortical GABAergic interneurons (INs) are generated in the medial ganglionic eminence (MGE) and migrate tangentially into cortex. Because most, if not all, migrating MGE-derived INs express the neuregulin (NRG) receptor, ErbB4, we investigated influences of Nrg1 isoforms and Nrg3 on IN migration through ventral telencephalon (vTel) and within cortex.ResultsDuring IN migration, NRG expression domains and distributions of ErbB4-expressing, MGE-derived INs are complementary with minimal overlap, both in vTel and cortex. In wild-type mice, within fields of NRG expression, these INs are focused at positions of low or absent NRG expression. However, in ErbB4-/- HER4heart mutant mice in which INs lack ErbB4, these complementary patterns are degraded with considerable overlap evident between IN distribution and NRG expression domains. These findings suggest that NRGs are repellents for migrating ErbB4-expressing INs, a function supported by in vitro and in vivo experiments. First, in collagen co-cultures, MGE-derived cells preferentially migrate away from a source of secreted NRGs. Second, cells migrating from wild-type MGE explants on living forebrain slices from wild-type embryonic mice tend to avoid endogenous NRG expression domains, whereas this avoidance behavior is not exhibited by ErbB4-deficient cells migrating from MGE explants and instead they have a radial pattern with a more uniform distribution. Third, ectopic NRG expression in the IN migration pathway produced by in utero electroporation blocks IN migration and results in cortex distal to the blockade being largely devoid of INs. Finally, fewer INs reach cortex in ErbB4 mutants, indicating that NRG-ErbB4 signaling is required for directing IN migration from the MGE to cortex.ConclusionsOur results show that NRGs act as repellents for migrating ErbB4-expressing, MGE-derived GABAergic INs and that the patterned expression of NRGs funnels INs as they migrate from the MGE to their cortical destinations.

Neuregulin-ERBB Signaling in the Nervous System and Neuropsychiatric Diseases

“…In one, Erbb4-expressing interneurons, in response to attractive, soluble Nrg1 Type I in the cortex, migrate on a permissive corridor of Nrg1 Type III through the developing striatum (Flames et al, 2004). In the other, Nrg1 and Nrg3 act as repellants that funnel interneurons as they migrate from the MGE to cortical destinations (Li et al, 2012a). Regardless, GABAergic interneurons are reduced in the cortex of Erbb4 mutant mice, which supports a role for Erbb4 in tangential migration (Fisahn et al, 2009; Flames et al, 2004; Li et al, 2012a; Schmucker et al, 2003).…”

“…In the other, Nrg1 and Nrg3 act as repellants that funnel interneurons as they migrate from the MGE to cortical destinations (Li et al, 2012a). Regardless, GABAergic interneurons are reduced in the cortex of Erbb4 mutant mice, which supports a role for Erbb4 in tangential migration (Fisahn et al, 2009; Flames et al, 2004; Li et al, 2012a; Schmucker et al, 2003). It remains unclear, however, if genesis and/or survival of interneurons are altered in the mutant.…”

“…Additionally, neuronal activity associated with limbic seizure increases Nrg1-Erbb4 signaling (Tan et al, 2012). Loss of Erbb4 from PV+ interneurons promotes kindling progression and leads to an increase of spontaneous seizures (Li et al, 2012b; Tan et al, 2012). …”

Neuregulin 3 Knockout Mice Exhibit Behaviors Consistent with Psychotic Disorders

“…However, the long-term neurobehavioral effects of abolishing or diminishing levels of NRG3 in the brain have not been tested. In order to address this question, we generated a mouse model with a deletion of the Nrg3 gene and tested for neurobehavioral phenotypes [22]. We found that Nrg3 knockout (KO) mice displayed novelty-induced hyperactivity, impaired prepulse inhibition (PPI) of the acoustic startle response, and deficient fear conditioning.…”

“…The NRG3 protein is a single-pass membrane protein with an extracellular N-terminal EGF-like domain that is cleaved to bind ErbB4 receptors [14,15,16], another schizophrenia susceptibility gene [17,18,19]. NRG3 and NRG1 are chemorepellant signals that guide GABAergic interneuron progenitors from their origin in the medial ganglionic eminence (MGE) through tangential migration to their final location in the developing cerebral cortex [20,21,22]. However, the long-term neurobehavioral effects of abolishing or diminishing levels of NRG3 in the brain have not been tested.…”