{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T11:07:21Z","timestamp":1792753641338,"version":"4.5.0"},"reference-count":95,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T00:00:00Z","timestamp":1739232000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:p>Rare neurodevelopmental disorders (NDDs) are one of the most significant unmet challenges in healthcare due to their lifelong nature, high management costs, and recurrence within families. This review will focus on newly-emerging genetic forms of NDDs resulting from variants in the glycine receptor (GlyR) \u03b12 subunit gene. Studies using <jats:italic>Glra2<\/jats:italic> knockout mice have convincingly demonstrated that GlyR \u03b12 is essential for cortical interneuron migration and progenitor homeostasis. Genetic inactivation of GlyR \u03b12 impairs the capacity of apical progenitors to generate basal progenitors, resulting in an overall reduction of projection neurons in the cerebral cortex. As a result, microcephaly is observed in newborn <jats:italic>Glra2<\/jats:italic> knockout mice, as well as defects in neuronal morphology, increased susceptibility to seizures, and defects in novel object recognition, motor memory consolidation, righting reflexes, novelty-induced locomotion in the open field test, and motivational reward tasks. Consistent with these findings, we and others have identified missense variants and microdeletions in the human GlyR \u03b12 subunit gene (<jats:italic>GLRA2<\/jats:italic>) in individuals with autism spectrum disorder (ASD), developmental delay (DD) and\/or intellectual disability (ID), often accompanied by microcephaly, language delay and epilepsy. In this review, we highlight the critical role of the GlyR \u03b12 subunit revealed by knockout mice and our current understanding of GlyR \u03b12 pathomechanisms in human NDDs. Finally, we will consider the current gaps in our knowledge, which include: (i) Limited functional validation for GlyR \u03b12 missense variants associated with human NDDs; (ii) The lack of <jats:italic>gain-of-function<\/jats:italic> GlyR \u03b12 mouse models; (iii) Our limited knowledge of GlyR \u03b12 interacting proteins. We also highlight potential future developments in the field, including routes to personalized medicines for individuals with GlyR \u03b12 mutations.<\/jats:p>","DOI":"10.3389\/fnmol.2025.1550863","type":"journal-article","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T07:02:05Z","timestamp":1739257325000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["The emerging role of glycine receptor \u03b12 subunit defects in neurodevelopmental disorders"],"prefix":"10.3389","volume":"18","author":[{"given":"Sean D.","family":"Fraser","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"Harvey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,2,11]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1016\/0014-5793(91)80383-e","article-title":"Cloning of a glycine receptor subtype expressed in rat brain and spinal cord during a specific period of neuronal development","volume":"281","author":"Akagi","year":"1991","journal-title":"FEBS Lett."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"738","DOI":"10.1016\/j.celrep.2013.07.016","article-title":"Glycine receptor \u03b12 subunit activation promotes cortical interneuron migration","volume":"4","author":"Avila","year":"2013","journal-title":"Cell Rep."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"1696","DOI":"10.1038\/cdd.2014.75","article-title":"Glycine receptors control the generation of projection neurons in the developing cerebral cortex","volume":"21","author":"Avila","year":"2014","journal-title":"Cell Death Differ."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"8161","DOI":"10.1523\/jneurosci.1554-07.2007","article-title":"The role of the dorsal striatum in reward and decision-making","volume":"27","author":"Balleine","year":"2007","journal-title":"J. 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