In a groundbreaking study published in Translational Psychiatry, a team of researchers led by Banks, G. and colleagues has revealed novel insights into the multifaceted role of the murine ATP-binding cassette transporter C5 (Abcc5), also known as MRP5 or cMOAT. This transporter, previously studied predominantly in the context of drug resistance and cellular detoxification, now emerges as a pivotal molecular player in the intricate processes of memory consolidation, circadian rhythm modulation, and glutamatergic signaling within the mammalian brain. The findings, set to reshape our understanding of cognitive function and biological timing, pave the way for innovative therapeutic approaches targeting neuropsychiatric disorders.
The ATP-binding cassette (ABC) transporters represent a large family of proteins responsible for translocating various substrates across cellular membranes utilizing ATP hydrolysis. Abcc5/MRP5, expressed abundantly in neural tissue, had long been hypothesized to contribute primarily to the efflux of organic anions and nucleoside analogues. However, the recent data suggest that its functional repertoire extends into realms crucial for neuronal communication and plasticity. This paradigm shift underscores the interconnectedness of membrane transport mechanisms with synaptic physiology and behavioral outputs.
Central to the study’s narrative is memory consolidation, the fundamental process by which transient experiences are forged into long-lasting memories. Through a combination of genetic, electrophysiological, and behavioral assays performed on murine models deficient in Abcc5, the research team demonstrated clear impairments in both short- and long-term memory paradigms. Intriguingly, these deficits correlated not only with altered neurotransmitter dynamics but also with disruption in gene expression patterns associated with synaptic remodeling. This implicates Abcc5 as a critical integrator of signaling events necessary for the stabilization of memory engrams.
Circadian rhythms, the endogenous oscillations governing physiological and behavioral cycles, are finely tuned by a network of molecular clocks and environmental cues. The study uncovered a hitherto unrecognized role for Abcc5 in the regulation of these rhythms. Mice bearing targeted deletions of Abcc5 exhibited aberrant locomotor activity patterns, desynchronization of core clock gene expression in the suprachiasmatic nucleus, and altered melatonin secretion profiles. These findings highlight that beyond its transporter function, Abcc5 may modulate circadian homeostasis by influencing signaling pathways linked to neuronal excitability and rhythmic gene transcription.
Glutamatergic neurotransmission, mediated primarily by the excitatory neurotransmitter glutamate, forms the backbone of synaptic communication in the central nervous system. Banks and colleagues provided compelling evidence that Abcc5 regulates aspects of glutamate signaling, notably through its impact on glutamate receptor trafficking and synaptic vesicle cycling. Electrophysiological recordings revealed diminished excitatory postsynaptic potentials and impaired long-term potentiation (LTP) in hippocampal slices derived from Abcc5 knockout animals. These functional impairments dovetail with the cognitive deficits observed in vivo, reinforcing the transporter’s role in sustaining synaptic plasticity.
Delving into the molecular underpinnings, the researchers employed advanced proteomic analyses and identified disrupted clustering of NMDA and AMPA receptor subunits in the absence of Abcc5. Such alterations compromise synaptic strength and adaptability, integral components of memory encoding processes. Moreover, the team observed altered levels of intracellular signaling molecules such as CaMKII and CREB, which are well-established mediators of activity-dependent gene expression pertinent to learning and memory.
The link between Abcc5 function and circadian signaling was further explored through transcriptomic profiling, which revealed misexpression of clock genes including Per1, Cry1, and Bmal1. These deviations suggest that Abcc5 might be necessary for the precise temporal control of gene expression cycles that orchestrate physiological rhythms. Additionally, altered redox states and ATP availability observed in mutant mice point towards a metabolic dimension to Abcc5’s regulatory role, integrating energy dynamics with circadian biochemical cascades.
Of particular significance is the potential translational implication of these findings. Disruptions in memory consolidation and circadian dysregulation are hallmark features of numerous neuropsychiatric conditions such as Alzheimer’s disease, schizophrenia, and mood disorders. By identifying Abcc5 as a nodal point connecting these processes, the study beckons the development of pharmacological modulators aimed at optimizing transporter activity. Such interventions could restore synaptic efficacy and stabilize biological rhythms, offering multifactorial remediation for cognitive and affective symptoms.
The research also opens exciting avenues for the study of drug resistance phenomena in psychiatric treatment. Given that ABC transporters are known to influence the pharmacokinetics of many neuroactive compounds, Abcc5 might serve as a bridge linking membrane transporter function with therapeutic outcomes. Understanding this relationship could refine dosing protocols and improve the efficacy of existing medications targeting glutamatergic pathways or circadian regulators.
Methodologically, the study’s strength lies in its integrative approach, combining in vivo behavioral assessments with exhaustive molecular characterizations. Techniques such as in situ hybridization, high-resolution microscopy, and patch-clamp electrophysiology provided a comprehensive picture of how genetic ablation of Abcc5 culminates in altered neuronal circuits and behavioral phenotypes. This multi-tiered strategy established causal links rather than mere associations, strengthening the validity of the conclusions drawn.
Furthermore, the work contributes novel insights into the intracellular trafficking roles played by ABC transporters in neurons, a comparatively underexplored aspect of their function. The authors propose a model whereby Abcc5 participates in the recycling and surface expression of key synaptic proteins, potentially influencing receptor availability and synaptic strength. This mechanistic framework invites broader examination across other members of the ABC transporter family and their involvement in neural dynamics.
Notably, the discoveries elucidate how peripheral and central functions of transporters such as Abcc5 are intertwined. While traditionally associated with xenobiotic clearance and cellular protection, this study places Abcc5 squarely in the domain of neurophysiology, underscoring the protein’s dualistic nature. Understanding these diverse roles will be critical as the field moves toward precision medicine approaches in neurology and psychiatry.
The implications for circadian biology are equally profound. As global lifestyles increasingly encroach upon natural rhythms, understanding molecular players like Abcc5 that govern the internal clock becomes ever more pressing. The transporter’s influence on rhythmic gene expression and behavioral patterns suggests it might also mediate the impact of environmental stressors on circadian stability, providing a molecular target for interventions aimed at circadian misalignment.
In conclusion, the work by Banks et al. presents a compelling narrative that redefines the functional landscape of the Abcc5 ATP-binding cassette transporter within the mammalian brain. By bridging the realms of memory, circadian biology, and synaptic signaling, these findings propel Abcc5 from a peripheral actor to a central orchestrator of neural health and behavior. Future research focused on this transporter could unveil transformative strategies to combat cognitive decline and circadian disturbances associated with neuropsychiatric illnesses, heralding a new era in brain therapeutics.
Subject of Research: The role of the murine ATP-binding cassette transporter C5 (Abcc5/MRP5/cMOAT) in memory consolidation, circadian rhythm regulation, and glutamatergic signaling.
Article Title: The murine ATP-binding cassette transporter C5 (Abcc5/MRP5/cMOAT) plays a role in memory consolidation, circadian rhythm regulation and glutamatergic signalling.
Article References: Banks, G., Cyranka, M., Vedovato, N. et al. The murine ATP-binding cassette transporter C5 (Abcc5/MRP5/cMOAT) plays a role in memory consolidation, circadian rhythm regulation and glutamatergic signalling. Transl Psychiatry 15, 218 (2025). https://doi.org/10.1038/s41398-025-03438-9
Image Credits: AI Generated
