Altered neurobiological function of brainstem hypoglossal neurons in DiGeorge/22q11.2 Deletion Syndrome

Abstract

DiGeorge/22q11.2 Deletion Syndrome (22q11DS) is a common genetic microdeletion syndrome that underlies several neurodevelopmental disorders including autism, attention deficit/hyperactivity disorder, and schizophrenia. In addition to cognitive impairments, those with 22q11DS have disrupted feeding and swallowing from birth onward. This perinatal dysphagia significantly compromises nutritional status, impairs appropriate weight gain, and can lead to life threatening aspiration-based infections. Appropriately timed excitation and inhibition of brainstem hypoglossal motor neurons, which innervate tongue muscles, is essential for proper feeding and swallowing. In this study we have examined changes in hypoglossal motor neuron function in the LgDel mouse model of 22q11DS. Hypoglossal motor neurons from LgDel mouse pups have action potentials with afterhyperpolarizations, mediated by a large conductance charybdotoxin-sensitive Ca activated K current, that are significantly shorter in duration and greater in magnitude than those in wild type pups. In addition, the amplitude, but not frequency, of glutamatergic EPSCs is diminished, and GABAergic, but not glycinergic, neurotransmission to hypoglossal motor neurons was reduced in LgDel animals. These observations provide a foundation for understanding the neurological changes in hypoglossal motor neuron function and their contribution to swallowing abnormalities that occur in DiGeorge/22q11.2 Deletion Syndrome.

Brainstem organoids from human pluripotent stem cells contain neural crest population

“…A third potential application of the hBSOs lies in their utility in investigations into the interaction between the brainstem and neural crest cells. For example, brainstem functions are reported to be affected in representative neural crest disorders, DiGeorge syndrome and Waardenburg-Shah syndrome (Nusrat et al, 2018;Wang et al, 2017). Nonetheless, the disease models of such diseases have yet to be established and their pathologies remain to be known.…”

The strengths of the genetic approach to understanding neural systems development and function: Ray Guillery's synthesis

“…Joined by our collaborator Larry Rothblat, we assessed how diminished 22q11 gene dosage compromises cortico‐cortical connectivity via layer 2/3 cortical projection neurons and interneurons, and how these changes contribute to disrupted cognitive behaviors in LgDel mice (Meechan et al., ; Meechan, Tucker, Maynard, & LaMantia, ; Meechan, Rutz et al., 2015; Paronett et al., ). In addition, with Sally Moody and David Mendelowitz, we characterized development and function of cranial sensory and brainstem motor circuits for feeding and swallowing (Karpinski et al., ; LaMantia et al., ; Wang, Bryan, LaMantia, & Mendelowitz, ). We related a 22q11 deletion‐dependent disruption of RA‐mediated hindbrain patterning (Karpinski et al., ; LaMantia et al., ; Figure , bottom panel ) to pediatric dysphagia—feeding and swallowing difficulty—that complicates early life for children with 22q11.2 DS (Eicher et al., ), thus establishing the LgDel mouse as the first genetically defined animal model for perinatal dysphagia in a neurodevelopmental disorder (reviewed by LaMantia et al., ).…”

Defects in fetal mouth movement and pharyngeal patterning underlie cleft palate caused by retinoid deficiency.

“…Defects in spontaneous fetal mouth movement as a cause of cleft palate have been previously documented (Tsunekawa et al, 2005;Walker, 1969 Wang et al, 2017). It has been demonstrated that both the LgDel model and the Tbx1 mutant model exhibit hyoid defects.…”

“…K. Miller, 2009). Transgenic mice have helped to determine that the mechanism of dysphagia is a hypoglossal neurotransmission defect that impairs swallowing function (Karpinski et al, 2014;Wang, Bryan, LaMantia, & Mendelowitz, 2017).…”

“…The conclusions of these studies emphasize the importance of proper function of the nerves that innervate muscles involved in feeding and swallowing as well as show that loss of nerve function can be a sole cause swallowing difficulties in early post-natal life. (Wang et al, 2017).…”