Biology subjects

Heller, A. T.

Publications and source records attributed to Heller, A. T..

5 recordsLinked to original sources

bioRxiv2026

Dose dependent impact of global Cc2d1a reduction on cognitive, social, and metabolic phenotypes

Background Autism spectrum disorder (ASD) and Intellectual disability (ID) share an in-creased male prevalence, but the biological mechanisms underlying this male bias remain poorly understood. Mice deficient for CC2D1A, a protein scaffold mutated in ASD/ID, have shown multiple male-specific deficits both in ASD-like behaviors and in the regulation of neuronal intracellular signaling pathways. However, previous re-search relied on conditional knockout (cKO) models due to early postnatal lethality of global Cc2d1a KO strains. Thus, the ability to define the developmental impacts of CC2D1A LOF in mice has been limited. While generating a Cc2d1a knock-in strain with V5-HA epitope tags, we found that homozygous animals (Cc2d1aVH/VH) resulted in a hypomorph line that can be used to study developmental loss of CC2D1A. Methods We assessed gross morphology, behavior, and intracellular signaling in male and female Cc2d1aVH/VH animals, where only ~20% of CC2D1A is present. We then crossed this line with a null allele to obtain a more severe hypomorph (Cc2d1a-/VH) and explore phenotypic penetrance thresholds. In addition to the previous phenotypic characterization, we also assessed body composition, feeding, and molecular hall-marks of metabolic function in both sexes. Results We found that ~80% CC2D1A reduction in Cc2d1aVH/VH mice did not recapitu-late any of the behavioral or molecular disruptions seen in cKO models. In contrast, ~90% CC2D1A reduction in Cc2d1a-/VH mice resulted in ASD/ID-like behavioral phe-notypes in males, similar to those reported in cKO lines, with distinct intracellular sig-naling disruptions. Male and female Cc2d1a-/VH mice also showed subtle but signifi-cant adult weight deficits associated with distinct metabolic changes. Limitations These models still do not fully recapitulate the complete CC2D1A LOF found in patients. Due to the analysis of two independent strains over multiple metrics, these studies are not powered to compare statistical differences between sexes and data were analyzed in males and females independently. Conclusions We identified a strikingly narrow CC2D1A expression threshold for the emer-gence of ASD/ID-like behavioral deficits in males. In addition, we revealed a novel role for CC2D1A in adult weight gain. These mouse strains will be useful to better under-stand CC2D1A LOF phenotypes.

neuroscience↗

bioRxiv2025

Interactome Analysis of the CC2D1A Scaffold Reveals Novel Neuronal Interactions and a Postsynaptic Role

Loss of the protein scaffold Coiled-coil and C2 domain containing 1A (CC2D1A) leads to intellectual disability (ID), autism spectrum disorder (ASD), and other neurodevelopmental presentations in humans. CC2D1A interactions have been studied in different cell lines proposing diverse roles in endolysosomal maturation and intracellular signaling, but the composition and functional mechanisms of the CC2D1A interactome remain poorly understood, especially in the brain. We performed comprehensive proteomic analyses to characterize CC2D1A binding partners, first comparing immunoprecipitations with three different anti-CC2D1A antibodies in HEK293 cells and then probing the mouse hippocampus. In HEK cells, Gene Ontology (GO) analysis revealed broad interaction networks in the nucleus, mitochondrion, and cytoplasmic vesicles sharing functions in organelle organization, vesicle mediated transport, and protein metabolism. These are unified by the best characterized CC2D1A interactor, the ESCRT III component CHMP4B, and define a pleiotropic role for CC2D1A in membrane trafficking and protein homeostasis. In the hippocampus, using stringent criteria and additional controls, including a Cc2d1a hypomorph mouse line, we identified 10 high-confidence interactors in addition to CHMP4B (TNIK, G3BP2, CEP135, MAPKAP1, SHFL, PPT1, PNKD, VAMP5, and PPP6R2) revealing roles for RNA regulation and synaptic function. The HEK studies had also pointed to CC2D1B, the only paralog of CC2D1A, as an interactor. We confirmed that not only the two proteins can bind in the brain, but also localize in different synaptic compartments, showing that CC2D1A is uniquely enriched in the post-synapse. This supports a unique function of CC2D1A in regulation of synaptic transmission that could explain the more severe cognitive deficits in humans and mice upon its loss. To our knowledge these findings provide the most comprehensive characterization of the CC2D1A interactome to date, elucidating novel, multifaceted, and dynamic cellular functions, providing potential implications for its role in neurodevelop-mental disorders.

molecular biology↗

bioRxiv2023

Differential processing of delay versus uncertainty in male but not female 16p11.2 hemideletion mice

Neurodevelopmental disorders are associated with differences in learning and motivation that can influence executive function, including behavioral flexibility and decision making. 16p11.2 hemideletion is a chromosomal copy number variant that is linked to neurodevelopmental disorders. 16p11.2 hemideletion in mice has been previously found to produce male-biased changes in reward learning, but the link between this and altered flexible decision making is poorly understood. We challenged 16p11.2 hemideletion mice with two reward-guided decision making tasks assessing flexible decision making under cost, delay and probability discounting. Both tasks elicited long-term changes in flexible decision making that separated 16p11.2 hemideletion males from wildtype males. In delay discounting,16p11.2 hemideletion males had a stronger, less flexible preference for the large reward at long delays, and this effect was reduced as wildtype males adjusted their preference to match that of the hemideletion males. In probability discounting, 16p11.2 hemideletion males initially had a similar preference for seeking improbable large rewards as did wildtype males, but over time began to prefer certainty to a greater extent than did wildtype males. Female mice discounted similarly for delayed or risky rewards regardless of the presence of the copy number variant. We have previously seen that male 16p11.2 hemideletion mice commit fewer nonreinforced responses than male wildtype mice in an operant setting, which we replicate here in delay discounting, while the introduction of risky rewards eliminates genotype differences in nonreinforced responses. Overall these data suggest that 16p11.2 hemideletion in males leads to differential processing of costs of delay versus inconsistency, with greater aversion to uncertainty than delays, and greater behavioral control by cues that consistently predict an outcome.

animal behavior and cognition↗

bioRxiv2021

Sequential delay and probability discounting tasks in mice reveal anchoring effects partially attributable to decision noise

Delay discounting and probability discounting decision making tasks in rodent models have high translational potential. However, it is unclear whether the discounted value of the large reward option is the main contributor to variability in animals choices in either task, which may limit translatability to human discounting data. Male and female mice underwent sessions of delay and probability discounting in sequence to assess how choice behavior adapts over experience with each task. To control for "anchoring" (persistent choices based on the initial delay or probability), mice experienced "Worsening" schedules where the large reward was offered under initially favorable delay or probability conditions that became less favorable during testing, followed by "Improving" schedules where the large reward was offered under initially unfavorable conditions that improved over a session. During delay discounting, both male and female mice showed elimination of anchoring effects over training. In probability discounting, both sexes of mice continued to show some anchoring even after months of training. One possibility is that noisy action selection could contribute to these anchoring effects, rather than persistent fluctuations in value discounting. We fit choice behavior in individual animals using models that included both a value-based discounting parameter and a decision noise parameter that captured variability in choices deviating from value maximization. Changes in anchoring behavior over time were tracked by changes in our decision noise parameter, not the value parameter. Thus, changes in discounting behavior in mice can result from changes in exploration of the environment rather than changes in reward valuation.

animal behavior and cognition↗

bioRxiv2020

Digging behavior discrimination test to probe burrowing and exploratory digging in male and female mice

Digging behavior is often used to test motor function and repetitive behaviors in mice. Different digging paradigms have been developed for behaviors related to anxiety and compulsion in mouse lines generated to recapitulate genetic mutations leading to psychiatric and neurological disorders. However, the interpretation of these tests has been confounded by the difficulty of determining the motivation behind digging in mice. Digging is a naturalistic mouse behavior, that can be focused toward different goals, i.e. foraging for food, burrowing for shelter, burying objects, or even for recreation as has been shown for dogs, ferrets, and human children. However, the interpretation of results from current testing protocols assumes the motivation behind the behavior often concluding that increased digging is a repetitive or compulsive behavior. We asked whether providing a choice between different types of digging activities would increase sensitivity to assess digging motivation. Here, we present a test to distinguish between burrowing and exploratory digging in mice. We found that mice prefer burrowing when the option is available. When food restriction was used to promote a switch from burrowing to exploration, males readily switched from burrowing to digging outside, while females did not. In addition, when we tested a model of intellectual disability and autism spectrum disorder that had shown inconsistent results in the marble burying test, the Cc2d1a conditional knock-out mouse, we found greatly reduced burrowing only in males. Our findings indicate that digging is a nuanced motivated behavior and suggest that male and female rodents may perform it differently. Significance StatementDigging behavior is commonly assessed in mice to study features of neurodevelopmental, psychiatric and neurological disorder. However, existing digging assays fail to discriminate between types of digging complicating data interpretation. Here we present a modified digging behavior discrimination task that can produce sensitive results in 30 minutes with easy to gather measures, making it accessible to wide variety of labs and experimental paradigms.

neuroscience↗