LRRTM4: A Novel Regulator of Presynaptic Inhibition and Ribbon Synapse Arrangements of Retinal Bipolar Cells

• Published in: Neuron (Cambridge, Mass.) Mass.), 2020-03, Vol.105 (6), p.1007-1017.e5
• Main Authors: Sinha, Raunak, Siddiqui, Tabrez J., Padmanabhan, Nirmala, Wallin, Julie, Zhang, Chi, Karimi, Benyamin, Rieke, Fred, Craig, Ann Marie, Wong, Rachel O., Hoon, Mrinalini
• Format: Article
• Language: English
• Subjects: Animals; bipolar cell; Bipolar cells; Bipolar disorder; Dendrites; Female; GABA receptor; gamma-Aminobutyric Acid - metabolism; Gene expression; Glutamatergic transmission; Heparan sulfate; Inhibition; Kinases; LRRTM; Male; Membrane Proteins - biosynthesis; Membrane Proteins - genetics; Membrane Proteins - physiology; Mice; Mice, Knockout; Mice, Transgenic; Nerve Tissue Proteins - biosynthesis; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - physiology; Neural Inhibition - physiology; Presynapse; presynaptic inhibition; Presynaptic Terminals - physiology; Proteins; Receptor density; Receptors, GABA - metabolism; Receptors, GABA - physiology; Retina; Retina - metabolism; Retinal Bipolar Cells - physiology; ribbon synapse; Synapses; synaptic adhesion protein; Synaptic ribbons; Synaptogenesis; Vesicular Inhibitory Amino Acid Transport Proteins - genetics; γ-Aminobutyric acid A receptors; γ-Aminobutyric acid C receptors
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2019.12.028

LRRTM4 is a transsynaptic adhesion protein regulating glutamatergic synapse assembly on dendrites of central neurons. In the mouse retina, we find that LRRTM4 is enriched at GABAergic synapses on axon terminals of rod bipolar cells (RBCs). Knockout of LRRTM4 reduces RBC axonal GABAA and GABAC receptor clustering and disrupts presynaptic inhibition onto RBC terminals. LRRTM4 removal also perturbs the stereotyped output synapse arrangement at RBC terminals. Synaptic ribbons are normally apposed to two distinct postsynaptic “dyad” partners, but in the absence of LRRTM4, “monad” and “triad” arrangements are also formed. RBCs from retinas deficient in GABA release also demonstrate dyad mis-arrangements but maintain LRRTM4 expression, suggesting that defects in dyad organization in the LRRTM4 knockout could originate from reduced GABA receptor function. LRRTM4 is thus a key synapse organizing molecule at RBC terminals, where it regulates function of GABAergic synapses and assembly of RBC synaptic dyads. •LRRTM4 is at presynaptic inhibitory synapses on retinal rod bipolar axon terminals•LRRTM4 regulates GABAA and GABAC synapse clustering and function at rod bipolar axons•Arrangement of synaptic ribbons at dyad configurations is disrupted without LRRTM4•Impaired GABAergic input onto bipolar terminals could underlie dyad mis-arrangements Sinha et al. show that the transsynaptic adhesion protein LRRTM4 regulates assembly and function of GABAergic synapses on retinal rod bipolar axons. Impaired GABAergic input onto rod bipolar axons also disrupts the arrangement of ribbon sites at specialized two-partner dyad synapses.