The role of agrin in synaptic development, plasticity and signaling in the central nervous system

Abstract

Development of the neuromuscular junction (NMJ) requires secretion of specific isoforms of the proteoglycan agrin by motor neurons. Secreted agrin is widely expressed in the basal lamina of various tissues, whereas a transmembrane form is highly expressed in the brain. Expression in the brain is greatest during the period of synaptogenesis, but remains high in regions of the adult brain that show extensive synaptic plasticity. The well-established role of agrin in NMJ development and its presence in the brain elicited investigations of its possible role in synaptogenesis in the brain. Initial studies on the embryonic brain and neuronal cultures of agrin-null mice did not reveal any defects in synaptogenesis. However, subsequent studies in culture demonstrated inhibition of synaptogenesis by agrin antisense oligonucleotides or agrin siRNA. More recently, a substantial loss of excitatory synapses was found in the brains of transgenic adult mice that lacked agrin expression everywhere but in motor neurons. The mechanisms by which agrin influences synapse formation, maintenance and plasticity may include enhancement of excitatory synaptic signaling, activation of the “muscle-specific” receptor tyrosine kinase (MuSK) and positive regulation of dendritic filopodia. In this article I will review the evidence that agrin regulates synapse development, plasticity and signaling in the brain and discuss the evidence for the proposed mechanisms.

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.…”

Presynaptic LRP4 promotes synapse number and function of excitatory CNS neurons

“…In Drosophila , the signal cannot be Agrin and in the mammalian CNS, Agrin is not essential for CNS synapse formation (Daniels, 2012). Thus, the Agrin-independence of CNS LRP4 may be conserved across systems.…”

Hippocampal Gene Expression Meta-Analysis Identifies Aging and Age-Associated Spatial Learning Impairment (ASLI) Genes and Pathways

“…Recent studies demonstrated a substantial loss of excitatory synapses in the adult transgenic mice brain that lacked agrin expression. Further, they demonstrated inhibition of synaptogenesis by agrin antisense oligonucleotides or agrin siRNA in neuronal cell culture (reviewed in [88]). L1cam promotes the outgrowth of neurites and thereby contributes to formation of neuronal connections, learning, and memory [89], [90] via activation of the mitogen-activated protein kinase (MAPK) pathway [91].…”