In a groundbreaking study poised to reshape our understanding of memory formation and cognitive sequencing, researchers have unveiled a critical molecular mechanism within the entorhinal cortex that governs how the brain encodes and processes sequential information. This discovery sheds new light on the neural circuitry involved in learning sequences, a fundamental aspect of cognition that underlies everything from language acquisition to navigation and complex decision-making. The novel findings highlight the pivotal role of the adhesion G protein-coupled receptor, known as Adgrl2, specifically expressed in layer III of the entorhinal cortex, and its indispensable function in orchestrating topographical circuit connectivity crucial for sequence learning.
The entorhinal cortex (EC) is a key brain region that interfaces between the hippocampus and neocortex, serving as a critical hub for memory consolidation and spatial navigation. Layer III neurons in the entorhinal cortex project extensively to the hippocampus, forming circuits that enable the temporal ordering of events—a process essential for constructing meaningful sequences from discrete memories. Until now, much of the molecular specificity governing the establishment and maintenance of these circuit connections remained elusive. This new research identifies Adgrl2 as a master regulator that ensures the correct wiring and functional integrity of these circuits, enabling precise sequential encoding.
To dissect the mechanistic role of Adgrl2, the researchers employed a combination of genetic, anatomical, and functional approaches in murine models. By selectively manipulating Adgrl2 expression in layer III of the entorhinal cortex, they were able to observe pronounced disruptions in the topographical organization of neuronal circuits. These disruptions translated into profound deficits in the animals’ ability to learn and recall sequences, as demonstrated by behavioral paradigms designed to test serial order memory and pattern completion. This causative link firmly positions Adgrl2 not merely as a peripheral molecule, but as a cornerstone for cognitive processes dependent on spatiotemporal patterning.
At the molecular level, Adgrl2 belongs to the family of adhesion G protein-coupled receptors (aGPCRs), which are increasingly recognized for their roles in neural development, synaptic adhesion, and signaling cascades. The receptor’s ability to facilitate cell-cell interactions and intracellular signaling pathways appears essential for guiding axonal projections and forming synaptic contacts with remarkable spatial precision. The research details how Adgrl2-dependent signaling modulates cytoskeletal dynamics and cell adhesion molecules that sculpt the entorhinal-hippocampal network architecture, essentially providing a molecular blueprint for the physical connectivity needed for sequence encoding.
Electrophysiological recordings revealed that circuits lacking Adgrl2 exhibited altered synaptic plasticity and firing patterns, impairing the temporal dynamics necessary for encoding ordered events. This aligns with the observed behavioral impairments, underscoring the functional consequences of disrupted topographical connectivity. Intriguingly, modulation of Adgrl2 pathways could potentially restore aspects of sequence learning, suggesting a targetable mechanism for cognitive enhancement or therapeutic intervention.
Beyond the immediate neurobiological impact, the discovery holds profound implications for neurological and psychiatric conditions characterized by impaired sequence learning and memory. Disorders such as Alzheimer’s disease, schizophrenia, and autism spectrum disorders often exhibit deficits in temporal processing and cognitive sequencing. The elucidation of Adgrl2’s role presents a new avenue for understanding the molecular underpinnings of these impairments and points toward future strategies aimed at modulating adhesion GPCR pathways to ameliorate symptoms.
The researchers further leveraged advanced imaging techniques to visualize how Adgrl2 expression dictates the spatial patterning of neuronal projections within the entorhinal cortex. Using high-resolution confocal microscopy combined with tract-tracing methods, they mapped the directional flow of information across layers and across the entorhinal-hippocampal axis. The resulting circuit diagrams unveiled a previously unappreciated degree of organizational specificity contingent upon Adgrl2 signaling, emphasizing the receptor’s role as a molecular architect in neural circuit formation.
Crucially, the temporal specificity of Adgrl2 expression was characterized during developmental windows corresponding to critical periods for circuit maturation. This temporal mapping revealed that disruptions in Adgrl2 distal to these periods resulted in less pronounced deficits, suggesting that its function is particularly vital during early postnatal phases when topographical connectivity patterns are established. These insights highlight the necessity of precise timing in therapeutic approaches aiming to modify Adgrl2-related pathways.
In dissecting the intracellular pathways downstream of Adgrl2 activation, the research team identified interactions with cytoskeletal regulators and canonical signaling cascades such as Rho GTPases and MAP kinases. These molecular intersections suggest that Adgrl2 orchestrates both the physical structuring of neural circuits and the dynamic synaptic signaling needed for plasticity. The dual role positions Adgrl2 as a nexus integrating structural and functional plasticity vital for the encoding and retrieval of ordered information.
The behavioral tasks employed in this study exemplify cutting-edge designs to probe sequence learning. Mice were exposed to odor and spatial sequence paradigms that require the hippocampus-dependent integration of temporally ordered stimuli. Performance deficits following Adgrl2 suppression underscore the receptor’s non-redundant role in high-order cognitive computation, affirming its essential contribution to the neural substrate of episodic memory and temporal context encoding.
From a translational perspective, the delineation of Adgrl2’s mechanism opens multiple lines of inquiry. Potential pharmacological agents that enhance or mimic Adgrl2 activity could be explored as cognitive enhancers for age-related memory decline or specific learning disabilities. Moreover, gene therapy vectors targeting entorhinal layer III neurons might be harnessed to restore defective circuitry in neurodegenerative diseases. These promising avenues will require detailed safety and efficacy assessments but represent a revolutionary shift toward molecularly targeted cognitive therapeutics.
The study also inspires a reevaluation of the entorhinal cortex’s role beyond spatial navigation, underscoring its broader function in temporally structured cognition. By establishing a molecular link between adhesion GPCR signaling and circuit topography, it reveals previously concealed layers of circuit specificity that underlie sequential learning—a cognitive dimension traditionally relegated to hippocampal studies. This expanded perspective could redefine research frameworks in systems neuroscience going forward.
In sum, this landmark research elucidates an intricate molecular and circuit-level mechanism by which Adgrl2 expression in entorhinal cortex layer III orchestrates the precise topography of neural connectivity vital for sequence learning. The comprehensive approach—spanning genetics, anatomy, physiology, and behavior—provides convergent lines of evidence positioning Adgrl2 as a keystone molecular player. This breakthrough advances both fundamental neuroscience and clinical understanding, paving the way for innovative strategies to enhance cognitive function and treat memory-related disorders.
As the field moves forward, further exploration into how Adgrl2 interacts with other adhesion molecules and neuromodulatory systems will be essential. Understanding whether similar mechanisms operate in other brain regions implicated in sequence processing could broaden the therapeutic scope. Moreover, long-term studies assessing how Adgrl2 modulation affects adult plasticity and memory consolidation are anticipated. These future directions promise to deepen our grasp of the molecular substrate of learning and memory, with profound scientific and societal implications.
This pioneering work not only enriches the biological tapestry of memory systems but also ignites hope for novel interventions in cognitive dysfunction. By marrying molecular neuroscience with behavioral analysis, it offers a model of how targeted research on brain circuitry can unravel the complex computations underlying human intelligence and adaptation. The scientific community eagerly anticipates the ripple effects of these discoveries across neuroscience, psychiatry, and beyond.
Subject of Research: Molecular and circuit mechanisms of sequence learning mediated by Adgrl2 expression in entorhinal cortex layer III.
Article Title: Entorhinal cortex layer III Adgrl2 expression controls topographical circuit connectivity required for sequence learning.
Article References:
Donohue, J.D., Blanton, C., Chen, A. et al. Entorhinal cortex layer III Adgrl2 expression controls topographical circuit connectivity required for sequence learning.
Transl Psychiatry 15, 272 (2025). https://doi.org/10.1038/s41398-025-03490-5
DOI: https://doi.org/10.1038/s41398-025-03490-5
