Reduced Brain Volume and White Matter Alterations in Shank3-Deficient Rats

Golden, Carla E. M.; Wang, Victoria X.; Harony‐Nicolas, Hala; Hof, Patrick R.; Buxbaum, Joseph D.

doi:10.21203/rs.3.rs-100329/v1

Cited by 4 publications

(3 citation statements)

References 14 publications

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“…While many neurodevelopmental milestones occur post-birth in rats (Zeiss 2021), the timing of our manipulation was selected to coincide with previous studies in which developmental disruptions between gestational day 11 and 21 produce robust neuropsychiatric alterations in adulthood, including autism-and schizophrenia-like phenotypes (Donegan et al 2020;Donegan, Boley, and Lodge 2018;Lodge 2013;Perez, Chen, and Lodge 2014). Indeed, lower total brain volume has been observed in rodent models of autism and early-life stress (Golden et al 2021;Reshetnikov et al 2021). Further, loss of brain volume in specific brain regions is observed in a variety of psychiatric illnesses (Steuber et al 2021;Su et al 2021;Angelescu et al 2021).…”

Section: Discussionmentioning

confidence: 99%

Gestational Buprenorphine Exposure Disrupts Dopamine Neuron Activity and Related Behaviors in Adulthood

Elam¹,

Donegan

Hsieh

et al. 2022

eNeuro

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Opioid misuse among pregnant women is rapidly increasing in the United States. The number of maternal opioid-related diagnoses increased by 131% in the last 10 years, resulting in an increased number of infants exposed to opioids in utero and a subsequent increase in infants developing neonatal abstinence syndrome (NAS). The most prescribed treatment to combat maternal opioid use disorder is buprenorphine, a partial μ-opioid receptor agonist and κ-opioid receptor antagonist. Buprenorphine treatment effectively reduces NAS but has been associated with disrupted cortical development and neurodevelopmental consequences in childhood. Less is known about the long-term neurodevelopmental consequences following buprenorphine exposure in utero . Previous research has shown that gestational buprenorphine exposure can induce anxiety-like and depressive-like phenotypes in adult rats, suggesting that exposure to buprenorphine in utero may render individuals more susceptible to psychiatric illness in adulthood. A common pathology observed across multiple psychiatric illnesses is dopamine system dysfunction. Here, we administered the highly-abused opioid, oxycodone (10 mg/kg, i.p.) or a therapeutic used to treat opioid use disorder, buprenorphine (1 mg/kg, i.p) to pregnant Sprague Dawley rats from gestational day 11 through 21, then examined neurophysiological alterations in the mesolimbic dopamine system and dopamine-dependent behaviors in adult offspring. We found that gestational exposure to buprenorphine or oxycodone increases dopamine neuron activity in adulthood. Moreover, prenatal buprenorphine exposure disrupts the afferent regulation of dopamine neuron activity in the ventral tegmental area (VTA). Taken together, we posit that gestational buprenorphine or oxycodone exposure can have profound effects on the mesolimbic dopamine system in adulthood.

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Section: Discussionmentioning

confidence: 99%

Gestational Buprenorphine Exposure Disrupts Dopamine Neuron Activity and Related Behaviors in Adulthood

Elam¹,

Donegan

Hsieh

et al. 2022

eNeuro

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“…It is possible that differences in superior colliculus or substantia nigra signaling or their connections might underlie some of the behavior differences reported here. While data is lacking in the literature as to the effect of Shank3 on SC function, Shank3 KO rats exhibit a lower relative volume of SC, suggesting that Shank3 loss may alter development of this brain region (Golden et al, 2021).…”

Section: Possible Circuit Mechanismsmentioning

confidence: 98%

Juvenile Shank3 KO Mice Adopt Distinct Hunting Strategies during Prey Capture Learning

Kuhnle

Grimes

Casanova

et al. 2022

eNeuro

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Mice are opportunistic omnivores that readily learn to hunt and eat insects such as crickets. The details of how mice learn these behaviors and how these behaviors may differ in strains with altered neuroplasticity are unclear. We quantified the behavior of juvenile wild type and Shank3 knockout mice as they learned to hunt crickets during the critical period for ocular dominance plasticity. This stage involves heightened cortical plasticity including homeostatic synaptic scaling, which requires Shank3, a glutamatergic synaptic protein that, when mutated, produces Phelan-McDermid syndrome and is often comorbid with autism spectrum disorder (ASD). Both strains showed interest in examining live and dead crickets and learned to hunt. Shank 3 knockout mice took longer to become proficient, and, after 5 days, did not achieve the efficiency of wild type mice in either time-to-capture or distance-to-capture. Shank3 knockout mice also exhibited different characteristics when pursuing crickets that could not be explained by a simple motor deficit. Although both genotypes moved at the same average speed when approaching a cricket, Shank3 KO mice paused more often, did not begin final accelerations toward crickets as early, and did not close the distance gap to the cricket as quickly as wild type mice. These differences in Shank3 KO mice are reminiscent of some behavioral characteristics of individuals with ASD as they perform complex tasks, such as slower action initiation and completion. This paradigm will be useful for exploring the neural circuit mechanisms that underlie these learning and performance differences in monogenic ASD rodent models. 3 Significance StatementDuring early development, activity-dependent plasticity mechanisms shape brain circuits.Shank3 is a synaptic protein that is mutated in Phelan-McDermid syndrome and is usually comorbid with autism spectrum disorder. Prior research shows that mice deficient in Shank3 exhibit abnormalities in a plasticity mechanism called homeostatic synaptic scaling. Here, we explore whether Shank3 knockout mice can learn to hunt crickets. We find that they can, although they pause more during their hunting and do not accelerate towards the cricket as rapidly. Future studies may be able to trace the neural circuits responsible for these differences, shedding more light on the causes of Phelan-McDermid syndrome and autism.

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“…Over 31 variants have been found in KMT2E, which plays a role in regulating histone methylation, in cases of ASD, with an estimated 45% macrocephaly penetrance 85 . Mutations in SHANK3, a postsynaptic scaffolding protein, are known to be causal in the ASD-M syndromic condition Phelan-McDermid syndrome 86 . WDFY3, which we recovered twice in our cohorts, encodes for an autophagy scaffolding protein 87 .…”

Section: (Which Was Not Certified By Peer Review) Preprintmentioning

confidence: 99%

A Subphenotype-to-Genotype Approach Reveals Disproportionate Megalencephaly Autism Risk Genes

Nishizaki

Mariano

et al. 2022

Preprint

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Among autistic individuals, a subphenotype with brain enlargement disproportionate to height (autism with disproportionate megalencephaly, or ASD-DM) seen at three years of age is associated with co-occurring intellectual disability and poorer prognoses later in life. However, many of the genes contributing to ASD-DM have yet to be delineated. In this study, we aim to identify additional ASD-DM associated genes to better define the genetic etiology of this subphenotype of autism. Here, we expand the previously studied sample size of ASD-DM individuals ten-fold by including probands from the Autism Phenome Project and Simons Simplex Collection, totaling 766 autistic individuals meeting the criteria for megalencephaly or macrocephaly and revealing 153 candidate ASD-DM genes harboring de novo protein-impacting variants. Our findings include thirteen high confidence autism genes and seven genes previously associated with DM. Five impacted genes have previously been associated with both autism and DM, including CHD8 and PTEN. By performing functional network analysis, we also narrowed in on additional candidate genes, including one previously implicated in ASD-DM (PIK3CA) as well as 184 additional genes previously implicated in ASD or DM alone. Using zebrafish as a model, we performed CRISPR gene editing to generate knockout animals for seven of candidate genes and assessed head-size and induced seizure activity differences. From this analysis, we identified significant morphological changes in zebrafish knockout models of two genes, ythdf2 and ryr3. While zebrafish knockout mutants model haploinsufficiency of assayed genes, we identified a de novo tandem duplication impacting YTHDF2 in an ASD-DM proband. Therefore, we also transiently overexpressed YTHDF2 by injection of in vitro transcribed human mRNA to simulate the patient-identified duplication. Following this, we observed increased head and brain size in the YTHDF2 overexpression zebrafish matching that of the proband, providing a functional link between YTHDF2 mutations and DM. Though discovery of additional mutations of ASD-DM candidate genes are required in order to fully elucidate the genetics associated with this severe form of autism, our study was able to provide support for YTHDF2 as a novel putative ASD-DM gene.

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Reduced Brain Volume and White Matter Alterations in Shank3-Deficient Rats

Cited by 4 publications

References 14 publications

Gestational Buprenorphine Exposure Disrupts Dopamine Neuron Activity and Related Behaviors in Adulthood

Gestational Buprenorphine Exposure Disrupts Dopamine Neuron Activity and Related Behaviors in Adulthood

Juvenile Shank3 KO Mice Adopt Distinct Hunting Strategies during Prey Capture Learning

A Subphenotype-to-Genotype Approach Reveals Disproportionate Megalencephaly Autism Risk Genes

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