Biology subjects

Sathler, M. F.

Publications and source records attributed to Sathler, M. F..

5 recordsLinked to original sources

bioRxiv2023

Prenatal exposure to valproic acid reduces synaptic δ-catenin levels and disrupts ultrasonic vocalization in neonates

Valproic acid (VPA) is an effective and commonly prescribed drug for epilepsy and bipolar disorder. However, children born from mothers treated with VPA during pregnancy exhibit an increased incidence of autism spectrum disorder (ASD). Although VPA may impair brain development at the cellular level, the mechanism of VPA-induced ASD has not been completely addressed. A previous study has found that VPA treatment strongly reduces {delta}-catenin mRNA levels in cultured human neurons. {delta}-catenin is important for the control of glutamatergic synapses and is strongly associated with ASD. VPA inhibits dendritic morphogenesis in developing neurons, an effect that is also found in neurons lacking {delta}-catenin expression. We thus hypothesize that prenatal exposure to VPA significantly reduces {delta}-catenin levels in the brain, which impairs glutamatergic synapses to cause ASD. Here, we found that prenatal exposure to VPA markedly reduced {delta}-catenin levels in the brain of mouse pups. VPA treatment also impaired dendritic branching in developing mouse cortical neurons, which was reversed by elevating {delta}-catenin expression. Prenatal VPA exposure significantly reduced synaptic AMPA receptor levels and postsynaptic density 95 (PSD95) in the brain of mouse pups, indicating dysfunctions in glutamatergic synaptic transmission. VPA exposure also significantly altered ultrasonic vocalization (USV) in newly born pups when they were isolated from their nest. Moreover, VPA-exposed pups show impaired hypothalamic response to isolation, which is required to produce animals USVs following isolation from the nest. Therefore, these results suggest that VPA-induced ASD pathology can be mediated by the loss of {delta}-catenin functions. HighlightsO_LIPrenatal exposure of valproic acid (VPA) in mice significantly reduces synaptic {delta}-catenin protein and AMPA receptor levels in the pups brains. C_LIO_LIVPA treatment significantly impairs dendritic branching in cultured cortical neurons, which is reversed by increased {delta}-catenin expression. C_LIO_LIVPA exposed pups exhibit impaired communication such as ultrasonic vocalization. C_LIO_LINeuronal activation linked to ultrasonic vocalization is absent in VPA-exposed pups. C_LIO_LIThe loss of {delta}-catenin functions underlies VPA-induced autism spectrum disorder (ASD) in early childhood. C_LI

neuroscience↗

bioRxiv2023

The autism-associated loss of δ-catenin functions disrupts social behaviors

{delta}-catenin is expressed in excitatory synapses and functions as an anchor for the glutamatergic AMPA receptor (AMPAR) GluA2 subunit in the postsynaptic density. The glycine 34 to serine (G34S) mutation in the{delta} -catenin gene is found in autism spectrum disorder (ASD) patients and induces loss of {delta}-catenin functions at excitatory synapses, which is presumed to underlie ASD pathogenesis in humans. However, how the G34S mutation causes loss of {delta}-catenin functions to induce ASD remains unclear. Here, using neuroblastoma cells, we discover that the G34S mutation generates an additional phosphorylation site for glycogen synthase kinase 3{beta} (GSK3{beta}). This promotes {delta}-catenin degradation and causes the reduction of {delta}-catenin levels, which likely contributes to the loss of {delta}-catenin functions. Synaptic {delta}-catenin and GluA2 levels in the cortex are significantly decreased in mice harboring the {delta}-catenin G34S mutation. The G34S mutation increases glutamatergic activity in cortical excitatory neurons while it is decreased in inhibitory interneurons, indicating changes in cellular excitation and inhibition. {delta}-catenin G34S mutant mice also exhibit social dysfunction, a common feature of ASD. Most importantly, inhibition of GSK3{beta} activity reverses the G34S-induced loss of {delta}-catenin function effects in cells and mice. Finally, using {delta}-catenin knockout mice, we confirm that {delta}-catenin is required for GSK3{beta} inhibition-induced restoration of normal social behaviors in {delta}-catenin G34S mutant animals. Taken together, we reveal that the loss of {delta}-catenin functions arising from the ASD-associated G34S mutation induces social dysfunction via alterations in glutamatergic activity and that GSK3{beta} inhibition can reverse {delta}-catenin G34S-induced synaptic and behavioral deficits. Significance Statement{delta}-catenin is important for the localization and function of glutamatergic AMPA receptors at synapses in many brain regions. The glycine 34 to serine (G34S) mutation in the{delta} -catenin gene is found in autism patients and results in the loss of {delta}-catenin functions. {delta}-catenin expression is also closely linked to other autism-risk genes involved in synaptic structure and function, further implying that it is important for the autism pathophysiology. Importantly, social dysfunction is a key characteristic of autism. Nonetheless, the links between {delta}-catenin functions and social behaviors are largely unknown. The significance of the current research is thus predicated on filling this gap by discovering the molecular, cellular, and synaptic underpinnings of the role of {delta}-catenin in social behaviors.

neuroscience↗

bioRxiv2022

HIV and FIV glycoproteins increase cellular tau pathology via cGMP-dependent kinase II activation

As the development of combination antiretroviral therapy (cART) against human immunodeficiency virus (HIV) drastically improves the lifespan of individuals with HIV, many are now entering the prime age when Alzheimers disease (AD)-like symptoms begin to manifest. Hyperphosphorylated tau, a known AD pathological characteristic, has been prematurely increased in the brains of HIV-infected patients as early as in their 30s and is increased with age. This thus suggests that HIV infection may lead to accelerated AD phenotypes. However, whether HIV infection causes AD to develop more quickly in the brain is not yet fully determined. Interestingly, we have previously revealed that viral glycoproteins, HIV gp120 and feline immunodeficiency virus (FIV) gp95, induce neuronal hyperexcitation via cGMP-dependent kinase II (cGKII) activation in cultured hippocampal neurons. Here, we use cultured mouse cortical neurons to demonstrate that HIV gp120 and FIV gp95 are sufficient to increase cellular tau pathology, including intracellular tau hyperphosphorylation and tau release to the extracellular space. We further reveal that viral glycoprotein-induced cellular tau pathology requires cGKII activation. Together, HIV infection likely accelerates AD-related tau pathology via cGKII activation.

neuroscience↗

bioRxiv2021

Loss of cGMP-dependent protein kinase II alters ultrasonic vocalizations in mice, a model for speech impairment in human microdeletion 4q21 syndrome

Chromosome 4q21 microdeletion leads to a human syndrome that exhibits restricted growth, facial dysmorphisms, mental retardation, and absent or delayed speech. One of the key genes in the affected region of the chromosome is PRKG2, which encodes cGMP-dependent protein kinase II (cGKII). Mice lacking cGKII exhibit restricted growth and deficits in learning and memory, as seen in the human syndrome. However, speech/vocalization impairments in these mice have not been determined. Moreover, the molecular pathway underlying speech impairment in humans is not fully understood. Here, we employed cGKII knockout (KO) mice as a model for the human microdeletion syndrome to test whether vocalizations are affected by loss of the PRKG2 gene. Mice emit ultrasonic vocalizations (USVs) to communicate in social situations, stress, and isolation. We thus recorded ultrasonic vocalizations as a model for speech in humans. We isolated postnatal day 5-7 pups from the nest to record and analyze USVs and found significant differences in vocalizations of KO mice relative to wild-type and heterozygous mutant mice. KO mice produced fewer calls that were shorter duration, higher frequency, and lower intensity. Because neuronal activity in the hypothalamus is important for the production of animal USVs following isolation from the nest, we assessed hypothalamic activity in KO pups following isolation. Indeed, we found abnormal hyperactivation of hypothalamic neurons in cGKII KO pups after isolation. Taken together, our studies indicate that cGKII is important for neuronal activation in the hypothalamus, which is required for the production of USVs in neonatal mice. We further suggest cGKII KO mice can be a valuable animal model for human microdeletion 4q21 syndrome. HighlightsO_LIChromosome 4q21 microdeletion leads to a human syndrome that exhibits restricted growth, mental retardation, and absent or delayed speech. C_LIO_LIThe cGMP-dependent protein kinase II (cGKII) gene is one of the genes located in the affected region of the chromosome. C_LIO_LIcGKII knockout mice show restricted growth and deficits in learning and memory. C_LIO_LIAltered ultrasonic vocalizations and abnormal activation in hypothalamic neurons are found when infant cGKII knockout pups are isolated from the nest. C_LIO_LIcGKII knockout mice can be a valuable animal model for human microdeletion 4q21 syndrome. C_LI

neuroscience↗

bioRxiv2020

Selective co-activation of α7- and α4β2-nicotinic acetylcholine receptors reverses beta-amyloid-induced synaptic dysfunction

Beta-amyloid (A{beta}) has been recognized as an early trigger in the pathogenesis of Alzheimers disease (AD) leading to synaptic and cognitive impairments. A{beta} can alter neuronal signaling through interactions with nicotinic acetylcholine receptors (nAChRs), contributing to synaptic dysfunction in AD. The three major nAChR subtypes in the hippocampus are composed of 7-, 4{beta}2-, and 3{beta}4-nAChRs. A{beta} selectively affects 7- and 4{beta}2-nAChRs, but not 3{beta}4-nAChRs in hippocampal neurons, resulting in neuronal hyperexcitation. However, how nAChR subtype selectivity for A{beta} affects synaptic function in AD is not completely understood. Here, we showed that A{beta} associated with 7- and 4-containing nAChRs but not 3-containing receptors. Computational modeling suggested two amino acids in 7-nAChRs, Arginine 208 and Glutamate 211, were important for the interaction between A{beta} and 7-containing nAChRs. These residues were found to be conserved only in the 7 and 4 subunits. We therefore mutated these amino acids in 7-containing nAChRs to mimic the 3 subunit and found that mutant 7-containing receptors were unable to interact with A{beta}, providing direct molecular evidence for how A{beta} selectively interacted with 7- and 4-containing receptors, but not 3-containing nAChRs. Selective co-activation of 7- and 4{beta}2-nAChRs was also sufficient to reverse A{beta}-induced AMPA receptor (AMPAR) dysfunction, including A{beta}-induced reduction of AMPAR phosphorylation and surface expression in hippocampal neurons. Moreover, the A{beta}-induced disruption of long-term potentiation was reversed by co-stimulation of 7- and 4{beta}2-nAChRs. These findings support a novel mechanism for A{beta}s impact on synaptic function in AD, namely the differential regulation of nAChR subtypes.

neuroscience↗