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SLITRK2 variants associated with neurodevelopmental disorders impair excitatory synaptic function and cognition in mice.

ABSTRACT: SLITRK2 is a single-pass transmembrane protein expressed at postsynaptic neurons that regulates neurite outgrowth and excitatory synapse maintenance. In the present study, we report on rare variants (one nonsense and six missense variants) in SLITRK2 on the X chromosome identified by exome sequencing in individuals with neurodevelopmental disorders. Functional studies showed that some variants displayed impaired membrane transport and impaired excitatory synapse-promoting effects. Strikingly, these variations abolished the ability of SLITRK2 wild-type to reduce the levels of the receptor tyrosine kinase TrkB in neurons. Moreover, Slitrk2 conditional knockout mice exhibited impaired long-term memory and abnormal gait, recapitulating a subset of clinical features of patients with SLITRK2 variants. Furthermore, impaired excitatory synapse maintenance induced by hippocampal CA1-specific cKO of Slitrk2 caused abnormalities in spatial reference memory. Collectively, these data suggest that SLITRK2 is involved in X-linked neurodevelopmental disorders that are caused by perturbation of diverse facets of SLITRK2 function.

SUBMITTER: El Chehadeh S

PROVIDER: S-EPMC9287327 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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SLITRK2 variants associated with neurodevelopmental disorders impair excitatory synaptic function and cognition in mice.

El Chehadeh Salima S Han Kyung Ah KA Kim Dongwook D Jang Gyubin G Bakhtiari Somayeh S Lim Dongseok D Kim Hee Young HY Kim Jinhu J Kim Hyeonho H Wynn Julia J Chung Wendy K WK Vitiello Giuseppina G Cutcutache Ioana I Page Matthew M Gecz Jozef J Harper Kelly K Han Ah-Reum AR Kim Ho Min HM Wessels Marja M Bayat Allan A Jaén Alberto Fernández AF Selicorni Angelo A Maitz Silvia S de Brouwer Arjan P M APM Silfhout Anneke Vulto-van AV Armstrong Martin M Symonds Joseph J Küry Sébastien S Isidor Bertrand B Cogné Benjamin B Nizon Mathilde M Feger Claire C Muller Jean J Torti Erin E Grange Dorothy K DK Willems Marjolaine M Kruer Michael C MC Ko Jaewon J Piton Amélie A Um Ji Won JW

Nature communications 20220715 1

SLITRK2 is a single-pass transmembrane protein expressed at postsynaptic neurons that regulates neurite outgrowth and excitatory synapse maintenance. In the present study, we report on rare variants (one nonsense and six missense variants) in SLITRK2 on the X chromosome identified by exome sequencing in individuals with neurodevelopmental disorders. Functional studies showed that some variants displayed impaired membrane transport and impaired excitatory synapse-promoting effects. Strikingly, th ...[more]

PMID: 35840571

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Project description:A potential link between GABRD encoding the δ subunit of extrasynaptic GABAA receptors and neurodevelopmental disorders has largely been disregarded due to conflicting conclusions from early studies. However, we identified seven heterozygous missense GABRD variants in 10 patients with neurodevelopmental disorders and generalized epilepsy. One variant occurred in two sibs of healthy parents with presumed somatic mosaicism, another segregated with the disease in three affected family members, and the remaining five occurred de novo in sporadic patients. Electrophysiological measurements were used to determine the functional consequence of the seven missense δ subunit variants in receptor combinations of α1β3δ and α4β2δ GABAA receptors. This was accompanied by analysis of electroclinical phenotypes of the affected individuals. We determined that five of the seven variants caused altered function of the resulting α1β3δ and α4β2δ GABAA receptors. Surprisingly, four of the five variants led to gain-of-function effects, whereas one led to a loss-of-function effect. The stark differences between the gain-of-function and loss-of function effects were mirrored by the clinical phenotypes. Six patients with gain-of-function variants shared common phenotypes: neurodevelopmental disorders with behavioural issues, various degrees of intellectual disability, generalized epilepsy with atypical absences and generalized myoclonic and/or bilateral tonic-clonic seizures. The EEG showed qualitative analogies among the different gain-of-function variant carriers consisting of focal slowing in the occipital regions often preceding irregular generalized epileptiform discharges, with frontal predominance. In contrast, the one patient carrying a loss-of-function variant had normal intelligence and no seizure history, but has a diagnosis of autism spectrum disorder and suffers from elevated internalizing psychiatric symptoms. We hypothesize that increase in tonic GABA-evoked current levels mediated by δ-containing extrasynaptic GABAA receptors lead to abnormal neurotransmission, which represent a novel mechanism for severe neurodevelopmental disorders. In support of this, the electroclinical findings for the gain-of-function GABRD variants resemble the phenotypic spectrum reported in patients with missense SLC6A1 (GABA uptake transporter) variants. This also indicates that the phenomenon of extrasynaptic receptor overactivity is observed in a broader range of patients with neurodevelopmental disorders, because SLC6A1 loss-of-function variants also lead to overactive extrasynaptic δ-containing GABAA receptors. These findings have implications when selecting potential treatment options, as a substantial portion of available antiseizure medication act by enhancing GABAergic function either directly or indirectly, which could exacerbate symptoms in patients with gain-of-function GABRD variants.

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SLITRK2 variants associated with neurodevelopmental disorders impair excitatory synaptic function and cognition in mice.

Publications

SLITRK2 variants associated with neurodevelopmental disorders impair excitatory synaptic function and cognition in mice.

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