Synaptic transmission is impaired at neuronal autonomic synapses in agrin‐null mice

Abstract

Neuronal synapse formation is a multistep process regulated by several pre- and postsynaptic adhesion and signaling proteins. Recently, we found that agrin acts as one such synaptogenic factor at neuronal synapses in the PNS by demonstrating that structural synapse formation is impaired in the superior cervical ganglia (SCG) of z+ agrin-deficient mice and in SCG cultures derived from those animals. Here, we tested whether synaptic function is defective in agrin-null (AGD-/-) ganglia and began to define agrin's mechanism of action. Our electrophysiological recordings of compound action potentials showed that presynaptic stimulation evoked action potentials in approximately 40% of AGD-/- ganglionic neurons compared to 90% of wild-type neurons; moreover, transmission could not be potentiated as in wild-type or z+ agrin-deficient ganglia. Intracellular recordings also showed that nerve-evoked excitatory postsynaptic potentials in AGD-/- neurons were only 1/3 the size of those in wild-type neurons and mostly subthreshold. Consistent with these defects in transmission, we found an approximately 40-50% decrease in synapse number in AGD-/- ganglia and cultures, and decreased levels of differentiation at the residual synapses in culture. Furthermore, surface levels of acetylcholine receptors (AChRs) were equivalent in cultured AGD-/- and wild-type neurons, and depolarization reduced the synaptic localization of AChRs in AGD-/- but not wild-type neurons. These findings provide the first direct demonstration that agrin is required for proper structural and functional development of an interneuronal synapse in vivo. Moreover, they suggest a novel role for agrin, in stabilizing the postsynaptic density of nAChR at nascent neuronal synapses.

Dystroglycan mediates homeostatic synaptic plasticity at GABAergic synapses

“…The effect of agrin on neuronal synapses is controversial. In peripheral ganglia, agrin participates in cholinergic synapse formation (38) but in the CNS its effects and effectors are unclear (39). We found that acute treatment with exogenous agrin was sufficient to induce a multiplicative scaling of inhibitory synapses that resembles activitydependent scaling up.…”

Heparan Sulfate Proteoglycans

“…Agrn Agrin Null allele: embryonic lethal; reduced number, size, and density of postsynaptic acetylcholine receptor aggregates in muscles; abnormal intramuscular nerve branching and presynaptic differentiation (Gautam et al 1996(Gautam et al ,1999; smaller brains (Serpinskaya et al 1999); abnormal development of interneuronal synapses (Gingras et al 2007); increased resistance to excitotoxic injury (Hilgenberg et al 2002); reduced number of cortical presynaptic and postsynaptic specializations (Ksiazek et al 2007). Floxed allele: Inactivation in podocytes does not affect glomerular charge selectivity or glomerular architecture (Harvey et al 2007).…”

LG2 agrin mutation causing severe congenital myasthenic syndrome mimics functional characteristics of non-neural (z−) agrin

“…Agrin was originally identified as an essential regulator of neuromuscular synapse formation (Ngo et al 2007; Sanes and Lichtman 2001), and also may contribute to neuronal synapse formation in the peripheral and central nervous systems (Gingras et al 2002, 2007; Martin et al 2005; Ksiazek et al 2007; Matsumoto-Miyai et al 2009). At the developing neuromuscular junction (NMJ), motoneuron-derived agrin is secreted into the synaptic basal lamina, and promotes synaptic differentiation by signaling through a receptor complex consisting of muscle specific receptor tyrosine kinase (MuSK) and low density lipoprotein receptor-related protein 4 (Lrp4) (Glass et al 1996; Kim et al 2008; Zhang et al 2008).…”