KathrynAnn E. Odamah

NEXMIF is an X-linked gene implicated in encephalopathy with symptoms of autism spectrum disorder (ASD), intellectual disability, and seizures. Our previous work demonstrated that Nexmif knockout (KO) male mice show autistic-like behaviors and memory deficits, accompanied by significant abnormalities in neuronal development and function. However, to date there are no available therapeutics for NEXMIF-related disorders. Here, as a proof-of-concept study, we examined the effect of postnatal reintroduction of the NEXMIF gene as a strategy for rescuing the impaired cellular and behavioral phenotypes in KO mice. We find that injection of a human NEXMIF lentivirus into KO mouse brains at postnatal day 1 (P1) leads to a restoration in synaptic protein expression and formation of dendritic spines. More importantly, postnatal NEXMIF expression ameliorated behavioral defects in repetitive behavior, sociability, social novelty preference, and cognition at adolescent ages, in addition to restoring dysregulated gene expression. These findings suggest that gene reintroduction at a postnatal stage may serve as a rescue strategy for neurodevelopmental and behavioral deficits caused by NEXMIF deficiencies.

Decades of research attempting to slow the onset of Alzheimer’s disease (AD) indicates that a better understanding of memory will be key to the discovery of effective therapeutic approaches. Here, we ask whether prodromal neural network dysfunction might occur in the hippocampal trisynaptic circuit by using α5IA as a selective negative modulator of extrasynaptic α5GABA-A receptors in TgF344-AD transgenic rats, a model for early onset AD. The results demonstrate that orally bioavailable α5IA, an established memory enhancer, increases CA1 pyramidal cell mean firing rates and peak CA1 ripple amplitude during wakeful immobility in wild type F344 rats resting in a familiar environment. We show that TgF344-AD rats, which express human amyloid-beta precursor protein (with the Swedish mutation) and human presenilin-1 (with a Δ exon 9 mutation), exhibit high serum Aβ42 and Aβ40 levels by 3 months of age. By 9 months of age, CA1 ripples in young adult TgF344-AD rats are nonresponsive to α5IA indicating network dysfunction prior to the onset of AD pathology and memory dysfunction. These results demonstrate, to the best of our knowledge, the first evidence for prodromal α5GABA-A receptor dysfunction in the AD hippocampal trisynaptic circuit. Moreover, as α5GABA-A receptors are located extrasynaptically and subserve the function of tonic inhibition we posit that an early stage of memory dysfunction involves the disruption of tonic inhibition in the hippocampus.