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Rescue of sexually dimorphic autistic-like abnormalities in mice carrying biallelic MDGA1 mutation by bazedoxifene

ABSTRACT: We understand that MDGA1 critically regulates GABAergic circuit disinhibition, but not whether and how MDGA1 dysfunction causes neurodevelopmental disorders. Here, we describe two patients with autism spectrum disorders (ASDs) carrying missense mutations in MDGA1: Val116Met/Ala688Val and Tyr635Cys/Glu756Gln. The Tyr635Cys/Glu751Gln substitution disrupts the triangular extracellular structure of MDGA1 and renders it unable to impact GABAergic synapses in hippocampal CA1 neurons. Murine in utero overexpression of MDGA1 Val116Met/Ala688Val alters normal cortical neuron migration and impairs ultrasonic vocalizations (USVs). Male Mdga1 knock-in (KI) mouse pups and adults harboring Tyr635Cys/Glu751Gln exhibit impaired USVs and sensorimotor gating, similar to male Mdga1 conditional knockout (cKO) mice. No behavioral deficit is seen in the females. Bazedoxifene (a selective estrogen receptor modulator) treatment of male Mdga1Y636C/E751Q KI mice restores the changes in expression and phosphorylation of a subset of GABAergic synaptic proteins, behaviors and GABAergic synaptic strength. Thus, different MDGA1 mutations manifest as distinct MDGA1 dysfunctions and likely cause ASDs via sexually dimorphic loss-of-function mechanisms.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Jin Young Kim

PROVIDER: MSV000096188 | MassIVE | Thu Oct 24 00:26:00 BST 2024

SECONDARY ACCESSION(S): PXD057136

REPOSITORIES: MassIVE

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Project description:Background: Mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) cause a severe neurological disorder characterised by early-onset epileptic seizures, autism and intellectual disability (ID). Impaired hippocampal function has been implicated in other models of monogenic forms of autism spectrum disorders and ID and is often linked to epilepsy and behavioural abnormalities. Many individuals with CDKL5 deficiency disorder (CDD) have null mutations and complete loss of CDKL5 protein, therefore in the current study we used a Cdkl5-/y rat model to elucidate the impact of CDKL5 loss on cellular excitability and synaptic function of CA1 pyramidal cells (PCs). We hypothesised abnormal pre and/or post synaptic function underlie the enhanced LTP we observe in the hippocampus of Cdkl5-/y rats. Methods: To allow cross-species comparisons of phenotypes associated with the loss of CDKL5, we generated a loss of function mutation in exon 5 of the rat Cdkl5 gene and assessed the impact of the loss of CDLK5 using a combination of extracellular and whole-cell electrophysiological recordings, biochemistry, and histology. Results: Our results indicate that CA1 hippocampal LTP is enhanced in slices prepared from juvenile, but not adult, Cdkl5-/y rats. Enhanced LTP does not result from changes in NMDA receptor function or subunit expression as these remain unaltered throughout development. Furthermore, Ca2+ permeable AMPA receptor mediated currents are unchanged in Cdkl5-/y rats. We observe reduced mEPSC frequency accompanied by increased spine density in basal dendrites of CA1 PCs, however we find no evidence supporting an increase in silent synapses when assessed using a minimal stimulation protocol in slices. Additionally, we found no change in paired-pulse ratio, consistent with normal release probability at Schaffer collateral to CA1 PC synapses. Conclusions: Our data indicate a role for CDKL5 in hippocampal synaptic function and raise the possibility that altered intracellular signalling rather than synaptic deficits contribute to the altered plasticity. Limitations: This study has focussed on the electrophysiological and anatomical properties of hippocampal CA1 PCs across early postnatal development. Studies involving other brains regions, older animals and behavioural phenotypes associated with the loss of CDKL5 are needed to understand the pathophysiology of CDD.

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Rescue of sexually dimorphic autistic-like abnormalities in mice carrying biallelic MDGA1 mutation by bazedoxifene

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