News and Publications

Lin, P.Y., Chen, L.Y., Jiang, M., Trotter, J.H., Seigneur, E., and Südhof, T.C. (2023) Neurexin-2: An Inhibitory Neurexin That Restricts Excitatory Synapse Formation in the Hippocampus. Sci. Advances 9, eadd8856. MCID: PMC9821874    

Neurexins are widely thought to promote synapse formation and to organize synapse properties. Here we found that in contrast to neurexin-1 and neurexin-3, neurexin-2 unexpectedly restricts synapse formation. In the hippocampus, constitutive or neuron-specific deletions of neurexin-2 nearly doubled the strength of excitatory CA3➔CA1 region synaptic connections and markedly increased their release probability. No effect on inhibitory synapses was detected. Stochastic optical reconstruction microscopy (STORM) superresolution microscopy revealed that the neuron-specific neurexin-2 deletion elevated the density of excitatory CA1 region synapses nearly twofold. Moreover, hippocampal neurexin-2 deletions also increased synaptic connectivity in the CA1 region when induced in mature mice and impaired the cognitive flexibility of spatial memory. Thus, neurexin-2 controls the dynamics of hippocampal synaptic circuits by repressing synapse assembly throughout life, a restrictive function that markedly differs from that of neurexin-1 and neurexin-3 and of other synaptic adhesion molecules, suggesting that neurexins evolutionarily diverged into opposing pro- and antisynaptogenic organizers.

An Inhibitory Neurexin That Restricts Excitatory Synapse Formation in the Hippocampus

Dai, J., Liakath-Ali, K., Golf, S., and Südhof, T.C. (2022) Distinct Neurexin-Cerebellin Complexes Control AMPA- and NMDA-Receptor Responses in a Circuit-Dependent Manner. E-Life 11, e78649. PMCID: PMC9586558    

At CA1→subiculum synapses, alternatively spliced neurexin-1 (Nrxn1SS4+) and neurexin-3 (Nrxn3SS4+) enhance NMDA-receptors and suppress AMPA-receptors, respectively, without affecting synapse formation. Nrxn1SS4+ and Nrxn3SS4+ act by binding to secreted cerebellin-2 (Cbln2) that in turn activates postsynaptic GluD1 receptors. Whether neurexin-Cbln2-GluD1 signaling has additional functions besides regulating NMDA- and AMPA-receptors, and whether such signaling performs similar roles at other synapses, however, remains unknown. Here, we demonstrate using constitutive Cbln2 deletions in mice that at CA1→subiculum synapses, Cbln2 performs no additional developmental roles besides regulating AMPA- and NMDA-receptors. Moreover, low-level expression of functionally redundant Cbln1 did not compensate for a possible synapse-formation function of Cbln2 at CA1→subiculum synapses. In exploring the generality of these findings, we examined the prefrontal cortex where Cbln2 was recently implicated in spinogenesis, and the cerebellum where Cbln1 is known to regulate parallel-fiber synapses. In the prefrontal cortex, Nrxn1SS4+-Cbln2 signaling selectively controlled NMDA-receptors without affecting spine or synapse numbers, whereas Nrxn3SS4+-Cbln2 signaling had no apparent role. In the cerebellum, conversely, Nrxn3SS4+-Cbln1 signaling regulated AMPA-receptors, whereas now Nrxn1SS4+-Cbln1 signaling had no manifest effect. Thus, Nrxn1SS4+- and Nrxn3SS4+-Cbln1/2 signaling complexes differentially control NMDA- and AMPA-receptors in different synapses in diverse neural circuits without regulating synapse or spine formation.

Distinct Neurexin-Cerebellin Complexes Control AMPA- and NMDA-Receptor Responses in a Circuit-Dependent Manner

Zhou, B., Lu, J.G., Siddu, A., Wernig, M., and Südhof, T.C. (2022) Synaptogenic Effect of APP-Swedish Mutation in Familial Alzheimer’s Disease. Science Transl. Medicine, 14, eabn9380. PMCID: PMC9894682    

Mutations in β-amyloid (Aβ) precursor protein (APP) cause familial Alzheimer's disease (AD) probably by enhancing Aβ peptides production from APP. An antibody targeting Aβ (aducanumab) was approved as an AD treatment; however, some Aβ antibodies have been reported to accelerate, instead of ameliorating, cognitive decline in individuals with AD. Using conditional APP mutations in human neurons for perfect isogenic controls and translational relevance, we found that the APP-Swedish mutation in familial AD increased synapse numbers and synaptic transmission, whereas the APP deletion decreased synapse numbers and synaptic transmission. Inhibition of BACE1, the protease that initiates Aβ production from APP, lowered synapse numbers, suppressed synaptic transmission in wild-type neurons, and occluded the phenotype of APP-Swedish-mutant neurons. Modest elevations of Aβ, conversely, elevated synapse numbers and synaptic transmission. Thus, the familial AD-linked APP-Swedish mutation under physiologically relevant conditions increased synaptic connectivity in human neurons via a modestly enhanced production of Aβ. These data are consistent with the relative inefficacy of BACE1 and anti-Aβ treatments in AD and the chronic nature of AD pathogenesis, suggesting that AD pathogenesis is not simply caused by overproduction of toxic Aβ but rather by a long-term effect of elevated Aβ concentrations.

Synaptogenic Effect of APP-Swedish Mutation in Familial Alzheimer’s Disease