LRRTM3 regulates activity-dependent synchronization of synapse properties in topographically connected hippocampal neural circuits

Abstract

Synaptic cell-adhesion molecules (CAMs) organize the architecture and properties of neural circuits. However, whether synaptic CAMs are involved in activity-dependent remodeling of specific neural circuits is incompletely understood. Leucine-rich repeat transmembrane protein 3 (LRRTM3) is required for the excitatory synapse development of hippocampal dentate gyrus (DG) granule neurons. Here, we report that Lrrtm3-deficient mice exhibit selective reductions in excitatory synapse density and synaptic strength in projections involving the medial entorhinal cortex (MEC) and DG granule neurons, accompanied by increased neurotransmitter release and decreased excitability of granule neurons. LRRTM3 deletion significantly reduced excitatory synaptic innervation of hippocampal mossy fibers (Mf) of DG granule neurons onto thorny excrescences in hippocampal CA3 neurons. Moreover, LRRTM3 loss in DG neurons significantly decreased mossy fiber long-term potentiation (Mf-LTP). Remarkably, silencing MEC–DG circuits protected against the decrease in the excitatory synaptic inputs onto DG and CA3 neurons, excitability of DG granule neurons, and Mf-LTP in Lrrtm3-deficient mice. These results suggest that LRRTM3 may be a critical factor in activity-dependent synchronization of the topography of MEC–DG–CA3 excitatory synaptic connections. Collectively, our data propose that LRRTM3 shapes the target-specific structural and functional properties of specific hippocampal circuits.

Trans‐synaptic mechanisms orchestrated by mammalian synaptic cell adhesion molecules

“…[87][88][89] Extensive anatomical analyses using LRRTM3 cKO mice demonstrated that LRRTM3 is required for maintaining excitatory synaptic inputs in both DG granule neurons and hippocampal CA3 pyramidal neurons. [88] In addition, LRRTM3 was shown to be required for maintaining normal synapse morphologies (i.e., MF boutons and thorny excrescences), as assessed by high-resolution three-dimensional scanning electron microscopy. [88] Electrophysiological recordings revealed that LRRTM3 is required to maintain LTP in the perforant and MF pathways.…”

“…APP acts as a presynaptic CAM to trans-synaptically regulate GABAergic synaptic strength and synapse number, and these parameters are negatively tuned by the action of postsynaptic MDGA1 in the dendritic, but not somatic, compartment of hippocampal CA1 pyramidal neurons (middle). AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxacolepropionic acid receptor; APP, amyloid precursor protein; CAM, cell adhesion molecule; Cbln, cerebellin precursor; DG, dentate gyrus; GABA A R, γ-aminobutyric acid type A receptor; GluD, glutamate receptor δ family; IgSF, immunoglobulin superfamily; LEC, lateral entorhinal cortex; LRRTM, leucine-rich repeat transmembrane protein; Lphn, latrophilin; MDGA1, MAM domain-containing glycosylphosphatidylinositol anchor protein 1; MEC, medial entorhinal cortex; NMDAR, N-methyl-D-aspartate receptor; Nrxn, neurexin; PV, parvalbumin; PTPσ, protein tyrosine phosphatase sigma; SLM, stratum lacunosum-moleculare; SP, stratum pyramidale; SO, stratum oriens; SR, stratum radiatum; SST, somatostatin; Sub, subiculum in the medial, but not lateral, perforant pathway, [88] indicating that LRRTM3 is critical in conferring neural circuit specificity. LRRTM3 cKO neurons exhibit enhanced neurotransmitter release, which might regulate the excitability of DG granule neurons and MF-LTP, [88] suggesting that medial perforant and MF pathways activities are inter-dependent.…”

“…Excitatory synaptic response & feedforward inhibition (DG → CA3 circuit) [99] LRRTM3 AMPAR-and NMDAR-mediated response (MEC → DG circuit) [88 ] MDGA1 Negative regulation of inhibitory synaptic strength & GABA release (SST + IN → CA1 PN circuit) [62] AMPAR, α-amino-3-hydroxy- showed that compartmentalized postsynaptic signaling is involved in synapse assembly, [14] it remains unclear how the various trans-synaptic signaling pathways contribute to shaping specific properties of neural circuits.…”

“…[88] Electrophysiological recordings revealed that LRRTM3 is required to maintain LTP in the perforant and MF pathways. [88] Intriguingly, LRRTM3 deletion in DG granule neurons reduces excitatory synapse number and excitatory synaptic strength PTPσ acts a presynaptic CAM to regulate neurotransmitter release, but does not regulate NMDAR functions at the CA1-Sub synapse type. APP acts as a presynaptic CAM to trans-synaptically regulate GABAergic synaptic strength and synapse number, and these parameters are negatively tuned by the action of postsynaptic MDGA1 in the dendritic, but not somatic, compartment of hippocampal CA1 pyramidal neurons (middle).…”

“…[ 84–86 ] In contrast, LRRTM3 and LRRTM4 appear to be non‐redundant in hippocampal DG granule neurons for regulating excitatory synaptic strength, long‐term synaptic plasticity, and neurotransmitter release, as shown in cKO mice lacking LRRTM3 or LRRTM4. [ 87–89 ]…”