Parahippocampal latrophilin-2 (ADGRL2) expression controls topographical presubiculum to entorhinal cortex circuit connectivity

Donohue, Jordan D.; Amidon, Ryan F; Murphy, Thomas R.; Wong, Anthony; Liu, Elizabeth D; Saab, Lisette; King, Alex J.; Pae, Haneal; Ajayi, Moyinoluwa T.; Anderson, Garret R.

doi:10.1016/j.celrep.2021.110031

Cited by 11 publications

(26 citation statements)

References 42 publications

(68 reference statements)

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“…Lphn2 encodes for the postsynaptic guidance molecule, Latrophilin-2. In dendritic layers of the hippocampus, latrophilin-2 is exclusively expressed in the CA1 SLM and acts as an axonal guidance molecule for inputs from the entorhinal cortex (Anderson et al, 2017; Donohue et al, 2021; Pederick et al, 2021). To understand if Lphn2 is topographically downregulated, CA1 SLM was microdissected from Pde1c-Cre -/- ;DTA and Pde1c-Cre +/- ;DTA groups at P15 and P30.…”

Section: Resultsmentioning

confidence: 99%

“…To understand if Lphn2 is topographically downregulated, CA1 SLM was microdissected from Pde1c-Cre -/-;DTA and Pde1c-Cre +/-;DTA groups at P15 and P30. Total RNA was extracted from the tissue and qRT-PCR analysis was performed targeting genes specific for CA1 synapses (Lphn2, (Donohue et al, 2021) Robo2 (Blockus et al, 2021) or CA3 synapses (Igsf8, Neo1 (Apóstolo et al, 2020)) to assess specificity of changes (Figure 4A). qRT-PCR analysis revealed that Lphn2 and Robo2 were both significantly upregulated at P15 Pde1c-Cre +/-;DTA compared to Pde1c-Cre -/-;DTA and conversely, were significantly downregulated at P30 Pde1c-Cre -/-;DTA compared to Pde1c-Cre -/-;DTA (Figure 4B).…”

Section: Slm Specific Effect Of Cr-cells Ablationmentioning

confidence: 99%

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Persistence of Cajal-Retzius cells in the postnatal hippocampus is required for development of dendritic spines of CA1 pyramidal cells

Glærum

Dunville

Montaldo

et al. 2022

Preprint

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SummaryCajal-Retzius (CR) cells are a transient type of neuron that populate the postnatal hippocampus. The role of transient cell types and circuits have been vastly addressed in neocortical regions, but poorly studied in the hippocampus. To understand how CR cells’ persistence influences the maturation of hippocampal circuits, we specifically ablated CR cells from the postnatal hippocampus. Our results highlighted layer-specific effects on dendritic spines and synaptic-related genes and revealed a critical role of CR cells in the establishment of the hippocampal network.

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Section: Resultsmentioning

confidence: 99%

Section: Slm Specific Effect Of Cr-cells Ablationmentioning

confidence: 99%

Persistence of Cajal-Retzius cells in the postnatal hippocampus is required for development of dendritic spines of CA1 pyramidal cells

Glærum

Dunville

Montaldo

et al. 2022

Preprint

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“…Additionally, as cell adhesion molecules, latrophilins interact via their N-terminal extracellular domain with four different families of interacting partners including neurexins (Boucard et al, 2012), teneurins (Silva et al, 2011), fibronectin leucine-rich transmembrane proteins (FLRTs) (O’Sullivan et al, 2012), and contactins (Zuko et al, 2016). In the central nervous system, latrophilins have been implicated in neuronal migration, circuit assembly, and synapse formation (Anderson et al, 2017; Del Toro et al, 2020; Donohue et al, 2021; Pederick et al, 2021; Sando and Südhof, 2021; Sando et al, 2019). In humans, mutation of LPHN3 is associated with increased risk of attention deficit/hyperactivity disorder and a missense variant in the LPHN2 gene is responsible for extreme microcephaly (Arcos-Burgos et al, 2010; Domené et al, 2011; Vezain et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Context-dependent requirement of G protein coupling for Latrophilin-2 in target selection of hippocampal axons

Pederick

Perry-Hauser

Meng

et al. 2022

Preprint

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The formation of neural circuits requires extensive interactions of cell-surface proteins to guide axons to their correct target neurons. Trans-cellular interactions of the adhesion G protein-coupled receptor latrophilin-2 (Lphn2) with its partner teneurin-3 instruct the precise assembly of hippocampal networks by reciprocal repulsion. Lphn2 acts as a receptor in distal CA1 neurons to direct their axons to proximal subiculum, and as a repulsive ligand in proximal subiculum to direct proximal CA1 axons to distal subiculum. It remains unclear if Lphn2-mediated intracellular signaling is required for its role in either context. Here, we show that Lphn2 couples to Gα12/13 in heterologous cells, which is increased by constitutive exposure of the tethered agonist. Specific mutations of Lphn2’s tethered agonist region disrupt its G protein coupling and autoproteolytic cleavage, whereas mutating the autoproteolytic cleavage site prevents cleavage but preserves a functional tethered agonist. Using an in vivo misexpression assay, we demonstrate that wild-type Lphn2 misdirects proximal CA1 axons to proximal subiculum and that Lphn2 tethered agonist activity is required for its role as a repulsive receptor. By contrast, neither tethered agonist activity nor autoproteolysis was necessary for Lphn2’s role as a repulsive ligand. Thus, tethered agonist activity is required for Lphn2-mediated neural circuit assembly in a context-dependent manner.

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“…From here we used the following formula for Corrected Total Fluorescence (CTF) = integrated density -(area of selected ROI X mean fluorescence of baseline/background readings). 44,45,46 This gave us the arbitrary units for average fluorescence intensity of our EYFP vs TdTomato terminals of interest.…”

Section: Fluorescence Intensity Calculationsmentioning

confidence: 99%

Hippocampal cells multiplex positive and negative engrams

Shpokayte

McKissick

Yuan

et al. 2020

Preprint

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The hippocampus is involved in processing a variety of mnemonic computations including the spatiotemporal components, as well as the corresponding emotional dimensions, of contextual memory.1–3 Recent studies have demonstrated vast structural and functional heterogeneity along the dorsal-ventral axis4 of the hippocampus, and while much is known about how the dorsal hippocampus processes spatial-temporal content, much less is known about whether or not the ventral hippocampus (vHPC) partitions positive and negative experiences into distinct sets of cells.4–9 Here, we combine transgenic and all-virus based activity-dependent tagging strategies to visualize multiple valence-specific engrams in the vHPC and demonstrate two partially segregated, albeit physiologically similar, populations that respond to positive and negative experiences. Next, using an RNA Sequencing approach, we find that vHPC positive and negative engram cells display distinct transcriptional programs in which neuroprotective- and neurodegenerative-related gene sets are enriched, respectively. Additionally, while optogenetic manipulation of tagged cell bodies in vHPC is not sufficient to drive behavior, tagged vHPC terminals projecting to the amygdala and nucleus accumbens, but not the prefrontal cortex, have the capacity to drive preference and avoidance when stimulated, as well as to “switch” or “reset” their capacity to drive either, thereby demonstrating their flexible contributions to behavior. We conclude that the vHPC contains genetically, cellularly, and behaviorally distinct populations of cells processing positive and negative memory engrams. Together, our findings provide a novel means by which to visualize multiple engrams within the same brain and point to their unique genetic signatures as putative avenues for future therapeutic interventions.One sentence summaryThe hippocampus contains neurons corresponding to positive and negative engrams, which are segregated by their molecular, cellular, and projection-specific features.

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Parahippocampal latrophilin-2 (ADGRL2) expression controls topographical presubiculum to entorhinal cortex circuit connectivity

Cited by 11 publications

References 42 publications

Persistence of Cajal-Retzius cells in the postnatal hippocampus is required for development of dendritic spines of CA1 pyramidal cells

Persistence of Cajal-Retzius cells in the postnatal hippocampus is required for development of dendritic spines of CA1 pyramidal cells

Context-dependent requirement of G protein coupling for Latrophilin-2 in target selection of hippocampal axons

Hippocampal cells multiplex positive and negative engrams

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