Biology subjects

Pederick, D. T.

Publications and source records attributed to Pederick, D. T..

7 recordsLinked to original sources

bioRxiv2026

Topographic CA1 input shapes subicular spatial coding

Precise anatomical topographic mapping in the brain supports high-fidelity information transfer for computations such as sensory alignment and motor coordination1,2. As a brain structure central to learning, memory, and navigation, the hippocampal formation is likewise organized with striking topographic precision3-8. Within this circuit, the subiculum plays a critical role in forming the cognitive map by integrating spatial and non-spatial information from both CA1 and the entorhinal cortex (EC)9-17. Inputs from these regions follow a continuous topography such that distal subiculum receives projections from proximal CA1 (pCA1) and medial EC (MEC), whereas proximal subiculum receives projections from distal CA1 (dCA1) and lateral EC (LEC)3-5,7,8. This anatomical architecture suggests that subicular computations may depend critically on the fidelity of these circuit topographies. However, because CA1 and EC provide partially overlapping spatial information, it remains unclear to what extent CA1-to-subiculum topography, independent of ECs contribution, shapes the physiological properties of subicular neurons. Here, by selectively disrupting CA1-to-subiculum topographic projections in latrophilin-2 conditional knockout mice, we show that precise topography shapes the anatomical distribution of subicular spatial coding while preserving single-cell tuning. Disrupted CA1 input topography also selectively impairs subicular boundary vector coding and long-term network stability. Thus, CA1 input topography is critical for organizing subicular spatial coding and network dynamics. HighlightsO_LICA1[->]subiculum topography organizes spatial coding distribution in the subiculum. C_LIO_LIDisrupted CA1 input topography spares individual subicular place cell tuning. C_LIO_LIDisrupted CA1 input topography selectively impairs subicular boundary vector coding. C_LIO_LILong-term subicular ensemble reactivation requires precise CA1 input topography. C_LI

neuroscience↗

bioRxiv2025

Inverse expression of Ten3 and Lphn2 across the developing mouse brain reveals a global strategy for circuit assembly

Precise wiring of neural circuits requires molecular strategies that ensure accurate target selection across diverse brain regions. Here, we identify inverse expression between a ligand-receptor pair, Teneurin-3 (Ten3) and Latrophilin-2 (Lphn2), across the developing mouse brain. Ten3 and Lphn2 exhibit inverse expression gradients along a retinotopic axis orthogonal to the ephrin-A and EphA gradients; along the tonotopic axis across multiple brainstem auditory nuclei; and along the dorsomedial-ventrolateral axis in striatum and pallidum. Their inverse expression also creates discrete domains of cerebellar Purkinje cells and cerebellar nuclei. Using conditional tag mice, we show that inverse Ten3 and Lphn2 expression patterns predict connectivity, following a Ten3[->]Ten3, Lphn2[->]Lphn2 rule in all above circuits, and that Lphn2 is required in executing this rule in Purkinje cells[->]cerebellar nuclei projection. Our findings suggest a global strategy of coordinating gene expression of key wiring molecules with circuit connectivity across the developing brain.

neuroscience↗

bioRxiv2025

Teneurin-3 and latrophilin-2 are required for somatotopic map formation and somatosensory topognosis

Somatotopy is a recurring organisational feature of the somatosensory system where adjacent neurons and their connections represent adjacent regions of the body. The molecular mechanisms governing the formation of such "body maps" remain largely unknown. Here we demonstrate that the cell surface proteins teneurin-3 and latrophilin-2 are expressed in opposing gradients aligning with the somatotopic map in the dorsal horn of the mouse spinal cord. Genetic manipulation of these proteins in spinal dorsal horn or sensory neurons distorts the somatotopy of neuronal connections and impairs accurate localisation of a noxious stimulus on the surface of the body. Our work provides the foundation for a molecular model of somatotopic map formation and insights into the role of somatotopic maps in the ability to accurately locate somatosensory stimuli or topognosis.

neuroscience↗

bioRxiv2025

Ten3-Lphn2-mediated target selection across the extended hippocampal network demonstrates a repeated strategy for circuit assembly

How do thousands of cell-surface proteins specify billions of neuronal connections in developing brains? We previously found that inverse expression of a ligand-receptor pair, teneurin-3 (Ten3) and latrophilin-2 (Lphn2) in CA1 and subiculum, instructs CA1[->]subiculum target selection through Ten3-Ten3 homophilic attraction and Ten3-Lphn2 heterophilic reciprocal repulsions. Here, we leveraged conditional knockouts to demonstrate that these mechanisms generalize to extended hippocampal networks, including entorhinal cortex and hypothalamus. Cooperation between attraction and repulsion differs depending on the order in which developing axons encounter the attractant and repellent subfields. Ten3 and Lphn2 can serve both as ligands for incoming axons and receptors for their own target selection, within the same neuron; Ten3 can be repulsive or attractive as ligand or receptor. Thus, multifunctionality and repeated use, together with recurrent circuit motifs prevalent in the brain, enable one ligand-receptor pair to instruct target selection of many more neurons.

neuroscience↗

bioRxiv2024

Functional analysis of the epilepsy gene Pcdh19 using a novel GFP-reporter mouse model

PCDH19 is a cell adhesion molecule belonging to the delta2-protocadherin subfamily that plays a critical role in brain development, neuronal migration, synaptic organisation, and neural circuit formation. Mutations in PCDH19 cause PCDH19-clustering epilepsy, an infantile-onset disorder characterized by seizures and intellectual disabilities. Despite the increasing development of constitutive cellular and murine models to investigate the effects of Pcdh19 knockout on cell-cell interactions and cellular function, the spatiotemporal consequences of its loss remain poorly understood. To address this gap, we generated and validated a novel conditional Pcdh19 knockout mouse model incorporating a GFP reporter (Pcdh19-cKO-GFP), enabling cell type-specific and temporally controlled gene deletion and direct visualization of recombination events. Using a neuronal Syn1-Cre driver, we demonstrate that targeted deletion of Pcdh19 in neurons results in altered hippocampal neurogenesis and mouse behaviour. We further demonstrate the versatility of this model using a doxycycline-inducible Cre system, enabling temporally controlled deletion of Pcdh19 and the modelling of disease-relevant phenotypes. Finally, we validate adeno-associated viral (AAV) vector-mediated recombination as a strategy for precise postnatal manipulation of Pcdh19 expression. Collectively, this Pcdh19-cKO-GFP model provides a powerful and flexible genetic tool to interrogate the cell type specific and temporary regulated functions of PCDH19 in the developing and postnatal brain under physiological and disease conditions.

neuroscience↗

bioRxiv2022

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

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 G12/13 in heterologous cells, which is increased by constitutive exposure of the tethered agonist. Specific mutations of Lphn2s 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 Lphn2s role as a repulsive ligand. Thus, tethered agonist activity is required for Lphn2-mediated neural circuit assembly in a context-dependent manner.

developmental biology↗

bioRxiv2020

Latrophilin-2 repels Teneurin-3+ hippocampal axons during target selection

Parallel information processing is a salient feature of complex nervous systems. For example, the medial and lateral hippocampal networks (MHN and LHN) preferentially process spatial- and object-related information, respectively. However, the mechanisms underlying parallel network assembly during development remain largely unknown. Here, we show that complementary expression of cell-surface molecules Teneurin-3 (Ten3) and Latrophilin-2 (Lphn2) in the MHN and LHN, respectively, guides the precise assembly of both the MHN and LHN. Viral-genetic perturbations in vivo demonstrate that Ten3+ axons are repelled by target-derived Lphn2, revealing that Lphn2/Ten3-mediated repulsion and Ten3/Ten3-mediated attraction cooperate to control precise target selection of MHN axons. In the LHN, Lphn2+ axons are confined to Lphn2+ targets via repulsion from Ten3+ targets. Our findings demonstrate that assembly of parallel hippocampal networks follows a Ten3[->]Ten3, Lphn2[->]Lphn2 rule instructed by reciprocal repulsions.

neuroscience↗