Reciprocal repulsions instruct the precise assembly of parallel hippocampal networks

Abstract

Mammalian medial and lateral hippocampal networks preferentially process spatial- and object-related information, respectively. However, the mechanisms underlying the assembly of such parallel networks during development remain largely unknown. Our study shows that, in mice, complementary expression of cell surface molecules teneurin-3 (Ten3) and latrophilin-2 (Lphn2) in the medial and lateral hippocampal networks, respectively, guides the precise assembly of CA1-to-subiculum connections in both networks. In the medial network, Ten3-expressing (Ten3+) CA1 axons are repelled by target-derived Lphn2, revealing that Lphn2- and Ten3-mediated heterophilic repulsion and Ten3-mediated homophilic attraction cooperate to control precise target selection of CA1 axons. In the lateral network, Lphn2-expressing (Lphn2+) CA1 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.

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

“…In fact, the absence of hippocampal CR cells resulted in a reduction of Lphn2. Lphn2 has been proposed to function as a postsynaptic guidance molecule for the hippocampal network, with peak expression at P8 during development (Pederick et al, 2021), and as an adhesion molecule for the maintenance of these connections in the adult (Anderson et al, 2017). The observed changes on Lphn2 suggest that CR cells contribute to the maturation of the entorhinal-hippocampal circuit also during postnatal development.…”

“…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.…”

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

“…The copyright holder for this preprint this version posted September 27, 2022. ; https://doi.org/10. 1101 We recently showed in mice that one of the three latrophilins, Lphn2, displays expression inverse to teneurin-3 (Ten3) in two parallel hippocampal networks (Pederick et al, 2021). While hippocampal Lphn2 is preferentially expressed in the distal CA1 and the proximal subiculum, Ten3 is enriched in the proximal CA1 and the distal subiculum.…”

To Stick or Not to Stick: The Multiple Roles of Cell Adhesion Molecules in Neural Circuit Assembly

“…Likewise in vitro , the close homolog of L1CAM, Chl1, engages in homophilic interactions to repel ventral midbrain dopaminergic axons ( Alsanie et al, 2017 ). Very recently, repulsive interactions between Tenm3 and Lphn2 were shown to topographically direct CA1 axons to the subiculum in the hippocampus ( Pederick et al, 2021 ; Figure 3C ). CAMs can instruct axon repulsion not only locally by signaling from the surface of cells or others axons, but also distally by acting as a gradient after shedding of their extracellular domain.…”

“…Conversely, distal CA1 (dCA1) axons expressing Lphn2 (pink) are repelled by Tenm3 in dSub (green) and project to pSub. Adapted from Pederick et al (2021) . (D) Clustered Pcdhs regulate self-avoidance.…”