The expanding roles of adhesion GPCRs in neural circuit assembly

Abstract

Bidirectional trans-synaptic signaling directs synapse formation and neural circuit assembly. Increasing evidence supports that several subfamilies of adhesion G protein-coupled receptors (aGPCRs) control important mechanistic aspects of synapse assembly and neural circuit wiring by combining trans-synaptic adhesion with G protein-coupled receptor signaling. These subfamilies include Latrophilins (ADGRL), CELSRs (cadherin EGF LAG 7-transmembrane receptors/ADGRC), and BAIs (brain angiogenesis inhibitors/ADGRB). Recently, aGPCRs have been linked to neurological disorders, further emphasizing the important roles of these receptors for proper neurological functions. Here, we discuss our current understanding of the functions of several aGPCRs in synaptic circuits and their links to neurological and neurodevelopmental disorders.

Graphical abstract

INTRODUCTION

The mammalian brain is composed of billions of neurons with diverse cell types that form neural circuits comprised of trillions of synaptic connections (Colón-Ramos, 2009). The proper establishment of synaptic connectivity is essential for proper neurological function, enabling our ability to engage with our environment, process pertinent information, and interact with the world around us (Luo, 2021). Despite this importance, the generation of these remarkably complex synaptic networks remains poorly understood (Südhof, 2018). Dr Roger Sperry’s “chemoaffinity hypothesis” in the 1950s states that molecular codes specify target recognition and circuit wiring (Sperry, 1951, Sperry, 1963). Recent evidence supports this hypothesis by showing that combinatorial codes comprised of extracellular proteins, including cell adhesion molecules, secreted factors, and cell surface receptors are central components of neural circuit formation (Südhof, 2021). However, the distinct intracellular signaling maps that correspond to these different codes remain understudied (Biederer and Stagi, 2008). Certain extracellular codes likely engage signaling pathways that direct shared synaptic assembly pathways (eg, active zone) while other combinatorial codes engage nonoverlapping pathways that mediate diversity and synaptic specificity (eg, postsynaptic scaffolds and neurotransmitter receptors).

Work over the past several decades has validated that combinatorial codes control synaptic properties and synapse assembly. The most notable example is presynaptic Neurexins and their array of postsynaptic ligands, including Neuroligins, Cerebellins, leucine-rich repeat transmembrane proteins, and Calsyntenins (Südhof, 2017). These interactions are intricately regulated by extensive alternative splicing, generating a synapse-specific molecular code that shapes synapse properties. However, extensive literature supports that Neurexins are likely not involved in the initial stages of synapse assembly, but rather the functional maturation and plasticity of synapses (Südhof, 2017, Varoqueaux et al., 2006). Conversely, recent work has implicated several subfamilies of adhesion G protein-coupled receptors (aGPCRs) as critical for synapse formation and neural circuit assembly in a manner that requires both extracellular adhesion and intracellular signaling (Fig. 1, Table 1).

Fig. 1.

Schematic diagrams of several aGPCRs with roles in neural circuit assembly. Domain organization of Lphns (Latrophilin/Adgrl), CELSRs (cadherin EGF LAG 7-transmembrane receptor/Adgrc), and BAIs (brain angiogenesis inhibitors/Adgrb). CAD, cadherin; EGF, epidermal growth factor; FLRTs, fibronectin leucine-rich repeat transmembrane proteins; GAIN, GPCR autoproteolysis-inducing; GPS-GPCR proteolysis site; HormR, hormone-binding region; Olf, olfactomedin; LamG, laminin G; NRXNs, Neurexin; NTD, N-terminal domain; PDZ, PSD95 DLG1 ZO-1; SP-signal peptide; TSR, thrombospondin type-1 repeats.

Table 1.

Summary of aGPCR studies in neural circuits

aGPCR	Circuits studied	Synaptic phenotypes	Synaptic localization	Neurological disease associations
Lphn1	Hippocampal cultures (Matúš et al., 2023)	Decreased inhibitory synapse density	Postsynaptic	Developmental delay, intellectual disability, ADHD, autism, epilepsy (Lei et al., 2025, Vitobello et al., 2022)
Lphn2	Hippocampal cultures, hippocampal CA1 region (Anderson et al., 2017, Sando et al., 2019), parallel-fiber to Purkinje cells (Zhang et al., 2020), medial entorhinal cortex layer III neurons (Donohue et al., 2025)	Decreased excitatory synapse density, decreased spine density selectively in stratum lac-mol, reduced excitatory transmission	Postsynaptic	Microcephaly (Vezain et al., 2018), addiction (Sun et al., 2020)
Lphn3	Hippocampal cultures, hippocampal CA1 region (Sando et al., 2019, Sando and Südhof, 2021), parallel-fiber to Purkinje cells (Zhang et al., 2020), human-induced neurons (Wang et al., 2024), cortex layer 2/3 to 5 (O’Sullivan et al., 2014), retinal cone synapses (Wang et al., 2021b)	Decreased excitatory synapse density, decreased spine density selectively in stratum radiatum, reduced excitatory transmission	Postsynaptic	ADHD (Arcos-Burgos and Muenke, 2010, Arcos-Burgos et al., 2010, Domené and Muenke , 2011, Huang et al., 2019, Labbe et al., 2012, Lange et al., 2012, Moreno-Salinas et al., 2022), addiction (Arcos-Burgos et al., 2019), autism (Chen et al., 2017)
Invertebrate Flamingo/FMI-1	Photoreceptor R cells (Chen and Clandinin, 2008), commissural neurons (Organisti et al., 2015), neuromuscular junction (Bao et al., 2007), GABAergic motor neurons (Najarro et al., 2012), left/right AIY neurons (Buyannemekh et al., 2025), zebrafish acoustic startle hindbrain circuit (Meserve et al., 2024)	Disrupted axonal targeting, disrupted target selection, decreased synapse density	N/A	N/A
CELSR1	Type II spiral ganglion neurons (Ghimire et al., 2018), facial brachiomotor neurons (Qu et al., 2010, Glasco et al., 2016)	Disrupted axonal targeting, altered neuronal migration,	N/A	Epilepsy (Bonardi et al., 2026, Chen et al., 2022), neural tube defects (Allache et al., 2012, Robinson et al., 2012)
CELSR2	Neocortex/cortico-striatal synapses (Li et al., 2022b), BLA-projecting IL PCF neurons (Freitas et al., 2024), zebrafish acoustic startle hindbrain circuit (Meserve et al., 2024), cultured hippocampal neurons (Shima et al., 2004)	Decreased spine density, altered glutamatergic transmission, decreased facial brachiomotor migration, decreased dendritic arborization	N/A	Epilepsy (Liu et al., 2025), neural tube defects (Chen et al., 2018, Tissir and Goffinet, 2010), Joubert syndrome (Vilboux et al., 2017)
CELSR3	Cultured hippocampal neurons (Shima et al., 2004, Thakar et al., 2017), hippocampal CA1 region (Thakar et al., 2017), several axonal fascicles in vivo (Tissir et al., 2005, Zhou et al., 2008)	Increased dendritic arborization, disrupted axonal development and targeting, reduced glutamatergic synapse density	N/A	Epilepsy (Li et al., 2022a), Tourette syndrome (Cadeddu et al., 2025, Nasello et al., 2024, Wang et al., 2018, Willsey et al., 2017), neural tube defects (Chen et al., 2018, Goffinet and Tissir, 2017)
BAI1	Type I spiral ganglion neurons (SGN) to inner hair cells (IHC) (Carlton et al., 2024), hippocampal CA1 region (Tu et al., 2018), human-induced neurons (Wang et al., 2021a), cultured hippocampal neurons (Duman et al., 2013)	Reduced AMPA receptor density, reduced spine density	Postsynaptic	Cancer (Cork and Van Meir, 2011, Moon et al., 2018, Nam et al., 2004), autism (Michaelson et al., 2012)
BAI2	Human-induced neurons (Wang et al., 2021a), cultured hippocampal neurons (Meyer et al., 2025)	Reduced excitatory synapse density	Postsynaptic	Cancer (Moon et al., 2018), progressive spastic paraparesis (Purcell and Hall, 2018)
BAI3	Climbing fiber to Purkinje cells (Aimi et al., 2023, Kakegawa et al., 2015, Sigoillot et al., 2015), human-induced neurons (Wang et al., 2021a), anterior olfactory nucleus to olfactory bulb (Wang et al., 2020)	Reduced synapse density, synaptic targeting deficits, reduced synaptic transmission	Postsynaptic	Schizophrenia (DeRosse et al., 2008, Lips et al., 2012), Cancer (Moon et al., 2018), intellectual disability (Scuderi et al., 2019)

ADHD, attention deficit and hyperactivity disorder; aGPCR, adhesion G protein-coupled receptor.

aGPCRs are 1 of the 5 GPCR families and contain 33 members divided into 9 subfamilies in humans (Hamann et al., 2015, Lala and Hall, 2022, Langenhan et al., 2013). aGPCRs share 3 general features—an extensive N-terminal extracellular region composed of multiple adhesion domains, an aGPCR signature GAIN (GPCR autoproteolysis-inducing) domain, and a subsequent 7TM (7-transmembrane) GPCR (Prömel et al., 2013). Furthermore, most aGPCRs display a large intracellular C-terminal tail that likely serves as a protein-protein interaction hub. Of these features, the GAIN is an evolutionarily conserved domain that has received attention due to its role in aGPCR signaling (Araç et al., 2012). Many aGPCR GAIN domains contain an autoproteolytic cleavage site, which generates a tethered agonist (TA), also known as the Stachel peptide (Liebscher and Schöneberg, 2016, Stoveken et al., 2015). Two models involving intramolecular TA-dependent signaling have been explored (Lala and Hall, 2022). In the dissociation model, adhesive force may remove the N-terminal fragment (NTF), exposing the TA and allowing it to engage the aGPCR orthosteric site to activate signaling. Conversely, the nondissociation model states that autoproteolytic cleavage and/or NTF removal is unnecessary for signaling via the TA. aGPCRs can also use other TA-independent mechanisms, including conformational coupling between the extracellular NTF and 7TM for transferring adhesion information to the GPCR to control signaling (Bui et al., 2023, Dates et al., 2024, Kishore et al., 2016, Kordon et al., 2023, Kordon et al., 2024, Salzman et al., 2017). Here, we discuss recent evidence implicating aGPCRs as essential molecular components of synapse formation and synaptic circuit assembly.

LATROPHILINS (LPHN)

Lphn/ADGRL was discovered in 1996 as a receptor for α-latrotoxin, a potent neurotoxin found in black widow spider venom that causes massive neurotransmitter release (Krasnoperov et al., 1997, Lelianova et al., 1997). Subsequent experiments identified Lphn as an aGPCR evolutionarily conserved between vertebrates and invertebrates, suggesting they may play critical biological functions throughout the phylogeny (Müller et al., 2015, Scholz et al., 2017). At first, Lphn was thought to be a presynaptic receptor, as α-latrotoxin potently triggers presynaptic neurotransmitter release (Ichtchenko et al., 1998, Krasnoperov et al., 1997, Lelianova et al., 1997). However, further research indicates that Lphn exhibits postsynaptic localization (Anderson et al., 2017, Matúš et al., 2024, Sando et al., 2019). There are 3 major mammalian paralogs (Lphn1, Lphn2, and Lphn3), and each paralog harbors a PDZ-binding motif shown to bind to postsynaptic SHANK proteins (Tobaben et al., 2000). SHANKs are postsynaptic scaffolds important for the synaptic localization of postsynaptic receptors, channels, and signaling enzymes. In addition, Lphn’s intracellular tail has been shown to exclusively phase separate postsynaptic scaffolds, suggesting that the recruitment of liquid-liquid phase-separated synaptic scaffolds to nascent synapses is a critical component of Lphn function in synapse assembly (Zhang et al., 2025).

Each of the 3 Lphn paralogs is comprised of the characteristic extracellular N-terminal region, GAIN domain, 7TM, and C-terminal tail mentioned above. The N-terminus contains 3 unique structures upstream of the GAIN domain, which include a hormone-binding region as well as the olfactomedin and lectin adhesion domains (Fig. 1). The olfactomedin and lectin domains bind to several presynaptic ligands, including presynaptic teneurins (Araç and Li, 2019, Boucard et al., 2014, Silva et al., 2011). Teneurins are large type II transmembrane proteins that contain 4 mammalian paralogs, each of which binds with high affinity to the lectin domain (Boucard et al., 2014, Li et al., 2018, Silva et al., 2011). The second major presynaptic ligand is fibronectin leucine-rich transmembrane proteins (FLRTs), which exhibit 3 mammalian paralogs (FLRT1-3) (O’Sullivan et al., 2012). Contrary to teneurin, FLRTs bind with high affinity to the olfactomedin domain (Lu et al., 2015). Finally, Neurexin is also known to form trans-cellular complexes with Lphn1 at the olfactomedin domain, although this interaction is currently the least understood of the 3 main trans-cellular ligands (Boucard et al., 2012). Given that FLRTs also bind to the olfactomedin, Neurexin and FLRTs may compete for Lphn binding, diversifying possible adhesion combinations.

Recent studies demonstrate that these interactions play a crucial role in neural circuit formation and synaptic specificity. In the mouse hippocampus, Lphn2 functions as a postsynaptic target recognition receptor for incoming entorhinal cortical axons onto the stratum lacunosum-moleculare layer of CA1 pyramidal neurons (Anderson et al., 2017). Here, Lphn2 deletion produces a ∼50% decrease in excitatory synapse and spine density from these inputs with no alterations in inhibitory synapses (Anderson et al., 2017). Conversely, postsynaptic Lphn3 is selectively targeted to the stratum oriens and stratum radiatum of CA1 pyramidal neurons, serving as a separate recognition receptor in nonoverlapping, complementary dendritic CA1 subregions (Sando et al., 2019, Sando and Südhof, 2021). These regions receive inputs from the CA3 Schaffer collaterals, a distinct pathway from the entorhinal cortical inputs into the stratum lacunosum-moleculare. Similar to Lphn2, Lphn3 deletion in CA1 neurons results in a ∼50% decrease in excitatory synapse density with no observable changes in inhibitory synapses (Sando et al., 2019, Sando and Südhof, 2021). Thus, the adhesion receptors Lphn2 and Lphn3 selectively direct the formation of perforant pathway and Schaffer collateral pathway synapses, respectively, onto hippocampal CA1 neurons. These findings indicate that postsynaptic aGPCR Lphn2/3 are coexpressed in the same neuron yet localized to discrete dendritic subregions, likely via either differential adhesion interactions or differential C-terminal tail interactions. These postsynaptic receptors then direct the formation of distinct presynaptic inputs into their respective subregions. Comparatively, postsynaptic Lphn1 is critical for perisomatic inhibitory synapses in hippocampal cells, suggesting a distinct function compared to Lphn2/3 (Matúš et al., 2023).

Mechanistically, Lphn3-dependent synaptic specificity requires the binding of both teneurins to the lectin domain and FLRTs to the olfactomedin domain, as the binding of both ligands serves as a coincidence detection mechanism (Sando et al., 2019). While all Lphns bind Teneurins and FLRTs in vitro, whether Lphn1 and Lphn2 synaptic function requires coincident binding to both partners remains to be explored. Furthermore, considering the distinct roles of Lphn1-3, they may interact with specific combinations of Teneurin and FLRT paralogs in vivo. Future studies are required to examine these possibilities. Intracellularly, the role of Lphn3 in synapse assembly also requires GPCR signaling (Fig. 2) (Sando and Südhof, 2021). Lphns have been shown to activate an array of G proteins (Camillo et al., 2021, Mathiasen et al., 2020, Nazarko et al., 2018, Ovando-Zambrano et al., 2019, Pederick et al., 2023, Sando and Südhof, 2021, Wang et al., 2024). Some of these G protein pathways, including Gαs/cAMP, have established roles in excitatory synapse formation (Kwon and Sabatini, 2011, Sando et al., 2022), while others, including Gα12/13, are important for inhibitory circuit assembly (Garbett et al., 2024). In addition to intracellular signaling, liquid-liquid phase separation of pre- and postsynaptic machinery is also involved in Lphn-teneurin function. The teneurin intracellular domain exclusively phase separates presynaptic active zone components, while Lphn exclusively recruits postsynaptic phase-separated condensates, enabling reconstitution of a rudimentary synaptic junction (Zhang et al., 2025). These findings support that the teneurin-Lphn complex recruits pre- and postsynaptic liquid-liquid phase-separated scaffolds to nascent synapses during synapse assembly. Thus, Lphn3 coordinates trans-synaptic adhesion with postsynaptic GPCR signaling and scaffold recruitment to control excitatory synapse assembly, though these data must be translated to Lphn1/2 as well as other brain regions. Furthermore, more work is needed to investigate the role of Lphn in synapse stabilization and elimination. Collectively, Lphns orchestrate an elaborate trans-synaptic complex also composed of teneurins, FLRTs, and possibly others (ie, Unc5d, Neurexins) into a trans-synaptic signaling and scaffolding apparatus that organizes excitatory synapse assembly and specificity (Fig. 2).

Fig. 2.

Model of Lphn3/FLRT/Teneurin function in synapse assembly. Postsynaptic Lphn3 engages both presynaptic FLRTs and Teneurins in a coincidence detection mechanism. Lphn3 function also requires GPCR-mediated signaling via G proteins and/or arrestins. The intracellular regions of Lphn3 or Teneurin cluster and phase separate postsynaptic or presynaptic scaffolds, respectively.

CELSRS (CADHERIN EGF LAG 7-TRANSMEMBRANE RECEPTORS)

CELSRs/ADGRC (invertebrate flamingo/cFMI-1/starry night) aGPCRs, such as Lphns, are highly conserved from invertebrates to vertebrates and have roles in neural circuit establishment (Boutin et al., 2012, Goffinet and Tissir, 2017). Mammalian CELSRs (CELSR1-3) display a large (∼2,450 amino acid) extracellular region which harbors 9 cadherin repeats, followed by EGF-like repeats, laminin G-like and laminin EGF-like domains, FBox, a hormone-binding region, and GAIN (Fig. 1). The CELSR1 and CELSR3 GAIN lacks autoproteolysis and TA-dependent activation (Bui et al., 2023). Furthermore, structural studies found that the ninth Cadherin repeat forms an interface with the GAIN, forming a compact module that regulates cell adhesion (Bandekar et al., 2025). The extracellular region of CELSR is comprised of 23 total domains, and these higher-order structures within large aGPCRs are likely essential for the coordination of adhesion and signaling.

Both the mammalian and invertebrate CELSR paralogs perform similar roles in axon outgrowth and circuit development. The invertebrate “Flamingo” (FMI-1) is largely associated with axonal guidance and synaptogenesis in Caenorhabditis elegans and Drosophila. FMI-1 mutants exhibit severe disruptions in Drosophila visual system topographic maps, suggesting a role in neuronal target selection during development (Lee et al., 2003, Li et al., 2019, Senti et al., 2003). Additionally, FMI-1 in Drosophila mediates commissural axon guidance through the Netrin/Frazzled attraction system, regulates synaptogenesis, and maintains axonal health at neuromuscular junctions (Bao et al., 2007, Organisti et al., 2015). Further studies found that Flamingo directs growth cone choice between correct postsynaptic partners, supporting functions in neural circuit establishment (Chen and Clandinin, 2008). In C elegans, FMI-1 performs a similar role in axonal guidance by regulating axonal projections in a left-right asymmetric manner (Buyannemekh et al., 2025, Chisholm et al., 2016, Loveless and Hardin, 2012, Steimel et al., 2010). cFMI-1 mutants show deficits in GABAergic motor neuron axonal pathfinding, decreased synapse density, and an accumulation of synaptic vesicles at nonsynaptic regions (Najarro et al., 2012).

In mammalian CELSR1-3, CELSR1 appears to demonstrate perhaps the least significance in synaptic function, as it mainly establishes epithelial planar cell polarity during the development of epithelial skin layers and hair follicles (Goffinet and Tissir, 2017). However, research has also found CELSR1 important for the migration of facial branchiomotor neurons during embryonic development (Goffinet and Tissir, 2017). In contrast, CELSR2 and CELSR3 potentially engage in cadherin domain-mediated homophilic interactions to mediate neural circuit development and dendritic arborization. Specifically, RNA interference experiments in rat neuronal cultures revealed that knockdown of CELSR2 greatly reduced dendritic arborization in both cortical pyramidal neurons and cerebellar Purkinje cells (Keeler et al., 2015, Shima et al., 2004, Shima et al., 2007). Opposingly, RNA interference-mediated knockdown of CELSR3 increased dendritic arborization, shown by higher levels of basal dendrites and greater branching complexity (Keeler et al., 2015, Shima et al., 2004, Shima et al., 2007). CELSR3 genetic deletion studies found that it is essential for axonal projections to the anterior commissure, subcerebral targets, and internal capsule (Tissir et al., 2005, Zhou et al., 2008). CELSR3 has also been shown to regulate glutamatergic synapse density in mice (Ban et al., 2021, Thakar et al., 2017). Moreover, while a potential homophilic interaction at synapses may result in CELSR pre- and postsynaptic localization, the precise synaptic localization of CELSRs has not been definitively characterized.

Growing literature is identifying CELSR1 and CELSR3 missense mutations associated with seizures and epilepsy, supporting that alterations in CELSR function contribute to neurological disorders (Chen et al., 2022, Liu et al., 2025, Li et al., 2022a). Collectively, evidence supports that CELSRs are important adhesion and signaling molecules in circuit assembly. While CELSR cadherins may participate in homophilic interactions, the large extracellular region likely generates interfaces for several currently unknown protein-protein interactions.

BAIS (BRAIN ANGIOGENESIS INHIBITORS)

BAI1-3/ADGRB1-3 aGPCRs contain an extracellular region with an N-terminal domain, thrombospondin type-1 repeats, a hormone-binding region, GAIN domain, the 7TM, and an intracellular tail with a PDZ-binding motif (Fig. 1). BAI1 localizes to the postsynaptic density, with BAI1 deletion altering the postsynaptic ultrastructure of CA1 pyramidal neurons and producing learning deficits (Zhu et al., 2015). Similarly, BAI2 and BAI3 are enriched in the postsynaptic compartment and are also important for excitatory synapse and spine density (Meyer et al., 2025). Thus, similar to Lphn2/3, BAIs are postsynaptic aGPCRs important for excitatory synapse formation.

The role of BAI3 in neural circuit assembly is regulated by its interaction with secreted C1ql proteins (Bolliger et al., 2011, Iijima et al., 2010, Martinelli et al., 2016). During development, a subset of climbing fiber connections onto Purkinje cells in the cerebellum are maintained while the remainder are eliminated. C1ql1 is a crucial anterograde signal controlling “single-winner” climbing fiber connectivity via interaction with postsynaptic BAI3 on Purkinje cells (Aimi et al., 2023, Kakegawa et al., 2015, Sigoillot et al., 2015). Furthermore, RTN4/NoGo receptors act as high-affinity ligands for BAIs in a manner that requires specific glycosylation patterns. This interaction is critical for neurite development and synapse formation (Wang et al., 2021a). Moreover, this finding prompts the premise that utilization of different glycosylation patterns may be used as an additional mechanism to generate synapse-specific diversity. Analogous to Lphns, postsynaptic BAI aGPCRs integrate several extracellular interactions to mediate excitatory synapse formation. Given BAI deletion causes a partial loss of excitatory synapses similar to Lphn2/3, whether BAIs and Lphns are localized to and important for the same or distinct populations of synapses is unclear.

OTHER AGPCRS

Several other aGPCR families are important not only for neural circuit assembly but for other critical aspects of neurodevelopment. One growing area is aGPCR function in glial cells. For example, ADGRG1 is crucial for oligodendrocyte development and myelination in several organisms (Ackerman et al., 2015, Giera et al., 2015). Moreover, ADGRV1 contributes to myelination in the auditory system (Shin et al., 2013). Several aGPCRs are important for peripheral nervous system myelination, including ADGRG1 and ADGRG6 (Ackerman et al., 2018, Mogha et al., 2016, Monk et al., 2009, Monk et al., 2011). ADGRG1 also has important roles in microglia, modulating circuits through synaptic elimination via the MYC transcription factor (Zhu et al., 2025). Many aGPCRs are expressed in non-neuronal cells and likely have currently unidentified functions within these cell types in shaping neural circuits.

AGPCRS IN NEUROLOGICAL DISORDERS

Lphn dysfunction is linked to various neurological disorders, including attention deficit and hyperactivity disorder (ADHD), autism spectrum disorder, and substance use disorder (Arcos-Burgos and Muenke, 2010, Arcos-Burgos et al., 2019, Arcos-Burgos et al., 2010, Bruxel et al., 2015, Bruxel et al., 2021, Domené and Muenke , 2011, Huang et al., 2019, Moreno-Salinas et al., 2019, Vitobello et al., 2022). Of these diseases, a growing number of studies associate Lphn3 with ADHD. Lphn3 deficits produce hyperactivity and alter motor behavior across several model organisms (Regan et al., 2021). In Drosophila, the mutation of the only Lphn homolog, dCirl, leads to abnormal locomotor movements, including conspicuous crawling patterns and less ambulatory distance traveled (Moreno-Salinas et al., 2019). Additionally, conditional dCirl knockdown induces hyperactivity and reduced average sleep time during the Drosophila night phase, both of which are indicative of an ADHD-like phenotype (van der Voet et al., 2016). In zebrafish, which harbor 2 Lphn paralogs (Lphn3.1 and Lphn3.2), Lphn3.1 knockdown causes increased swimming distances and general hyperactivity (Lange et al., 2012, Lange et al., 2018). This relationship is also seen in rodents, where Lphn3 loss-of-function studies lead to hyperactive rodent phenotypes with initial evidence implicating alterations in striatal circuits (Regan et al., 2021, Regan et al., 2022, Regan et al., 2019). Finally, numerous genetic studies associate the Lphn3 gene with the etiology of ADHD in humans (Bao et al., 2007, Buyannemekh et al., 2025, Chisholm et al., 2016, Keeler et al., 2015, Najarro et al., 2012, Shima et al., 2004). Several of these missense mutations impair G protein activation (Moreno-Salinas et al., 2022). Despite this growing evidence, the synapse-specific and mechanistic basis of Lphn3 in disease remains unknown. Recent studies also associate Lphn2 variants with cocaine use disorder (Sun et al., 2020), though these connections require more research.

A recent set of human genetics studies identify CELSR1-3 variants associated with febrile seizures and epilepsy (Chen et al., 2022, Liu et al., 2025, Li et al., 2022a). One CELSR3 missense mutation in epilepsy is within intracellular loop 3 (ICL3) of the 7TM GPCR, a region critical for G protein coupling, and 2 different mutations are present within the extracellular region. This indicates that disruptions in CELSR adhesion and/or signaling may alter synaptic physiology and increase susceptibility to seizures. ADGRV1 mutations are also linked to epilepsy, and mouse models exhibit increased propensity for audiogenic seizures (McMillan and White, 2004, Myers et al., 2018, Zhou et al., 2022). Despite the growing evidence supporting dysfunctions in aGPCRs in disease, there are currently no approved therapeutics targeting aGPCRs. This is striking considering that GPCRs are the largest FDA-approved drug targets. Currently, aGPCRs are inherently difficult to target with traditional small-molecule approaches, and our mechanistic understanding of how various aGPCRs contribute to psychiatric diseases is not properly understood. Thus, more research into the aGPCR signaling mechanisms, as well as different drug targeting strategies, is needed to develop new therapeutics against aGPCRs and disease.

CONCLUSIONS AND PERSPECTIVES

The underlying molecular mechanisms responsible for aGPCR function are incompletely understood. While aGPCRs possess various N-terminal adhesion domains that bind to trans-synaptic ligands, it is unknown how different combinations of these ligands may influence signaling and/or signaling bias, and the interplay between adhesion and TA-dependent or -independent activation. The precise downstream synaptic signaling cascades triggered by aGPCR activation are also enigmatic, and studying these signaling pathways is a critical next step toward understanding aGPCR function. The temporal aspects of aGPCR signaling are also understudied. As aGPCRs are implicated in synaptic assembly, it is important to understand how the timing of aGPCR activation during critical timepoints may impact synaptic maturation. Lastly, it is unknown how synaptic aGPCRs facilitate synaptic nano-organization. For example, aGPCRs may organize into nanocolumns at synapses or be involved in assembling nanocolumns. Future work will need to determine if certain aGPCRs are involved in synapse-specific organization at the nanoscale level.

Aside from aGPCR function, more work is required to investigate how aGPCRs could be targeted for novel therapeutic treatments. aGPCRs present unique, though challenging, drug targets due to many factors, including the similarity of the TA orthosteric site between different aGPCRs. This may render small molecules nonspecific, making these sites difficult to target directly. Furthermore, many aGPCRs are orphan receptors or have not been extensively studied, making therapeutic development even more difficult. Of the aGPCRs discussed, Lphn3 has a strong and growing link to ADHD and stimulant response. Multiple model organisms exhibit hyperactivity and altered locomotion following Lphn3 deletion, and human genetic studies have linked Lphn3 to ADHD etiology. Additionally, Lphn3 adhesion interactions and signaling are relatively well-studied, making Lphn3 a promising target for future therapeutic development.

Collectively, increasing evidence supports that aGPCRs integrate extracellular interactions with GPCR signaling to control critical aspects of synapse formation and neural circuit assembly. A deeper understanding of aGPCR function and signaling will inform mechanistic insights into how neural circuits are established and organized by synaptic connectivity.

Author Contributions

Shane Watson: Writing – review & editing. Richard C. Sando: Writing – review & editing, Writing – original draft.

Declaration of Competing Interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.