Synaptic Elimination in Neurological Disorders

Abstract

Synapses are well known as the main structures responsible for transmitting information through the release and recognition of neurotransmitters by pre- and post-synaptic neurons. These structures are widely formed and eliminated throughout the whole lifespan via processes termed synaptogenesis and synaptic pruning, respectively. Whilst the first process is needed for ensuring proper connectivity between brain regions and also with the periphery, the second phenomenon is important for their refinement by eliminating weaker and unnecessary synapses and, at the same time, maintaining and favoring the stronger ones, thus ensuring proper synaptic transmission. It is well-known that synaptic elimination is modulated by neuronal activity. However, only recently the role of the classical complement cascade in promoting this phenomenon has been demonstrated. Specifically, microglial cells recognize activated complement component 3 (C3) bound to synapses targeted for elimination, triggering their engulfment. As this is a highly relevant process for adequate neuronal functioning, disruptions or exacerbations in synaptic pruning could lead to severe circuitry alterations that could underlie neuropathological alterations typical of neurological and neuropsychiatric disorders. In this review, we focus on discussing the possible involvement of excessive synaptic elimination in Alzheimer's disease, as it has already been reported dendritic spine loss in post-synaptic neurons, increased association of complement proteins with its synapses and, hence, augmented microglia-mediated pruning in animal models of this disorder. In addition, we briefly discuss how this phenomenon could be related to other neurological disorders, including multiple sclerosis and schizophrenia.

Keywords: Synaptic elimination; alzheimer’s disease; complement cascade; microglia; multiple sclerosis; schizophrenia; synaptic plasticity..

Fig. (1)

Main mechanisms of synaptic elimination during development. Recent data have indicated a relevant role of immune molecules in developmental synaptic pruning. As it is shown here, astrocytes secrete TGF-β3, leading to the downstream upregulation of the complement component C1q by neurons. Once in the plasma membrane, C1q triggers the activation of the classical complement cascade later culminating in C3 accumulation, which is recognized by microglia via CR3, thus prompting the phagocytosis of target synapses. IL-33, another astrocytic-secreted factor, is essential for synaptic engulfment by microglial cells. In addition, MHC I and its binding partner PirB have been demonstrated to promote synaptic elimination, while pre-synaptic CD47 signals via SIRPα, inhibiting synaptic uptake by microglial cells. Finally, LTD induction, following NMDAR and group I mGluRs activation, is also capable of promoting synapse loss, while LTP inhibits this phenomenon. mGluRI: group I metabotropic glutamate receptor; NMDAR: N-methyl-D-aspartate receptor; MHC I: major histocompatibility complex class I; PirB: paired immunoglobulin-like receptor B; CR3: complement receptor 3; CD47: cluster of differentiation 47; SIRPα: signal-regulatory protein α; IL-33: interleukin 33; TGF-β3: transforming growth factor β3. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Fig. (2)

Activation of synaptic pruning mechanisms is relevant for AD progression. Progressive synaptic loss is one of the main morphological features of Alzheimer’s disease, observed even earlier than senile plaque deposition. Several studies have demonstrated the prominent role of the classical complement cascade in such event. Indeed, it has been shown that ApoE4, a major AD risk factor, leads to C1q accumulation in animal models. Additionally, mGluR1 activation allows a greater C1q mRNA translation by promoting the dephosphorylation of FMRP, an RNA-binding protein that represses translation. These data provide a suitable explanation for the increased levels of C1q and its downstream complement factor C3 in AD, which, in turn, trigger targeted synapses phagocytosis by microglial cells. Moreover, NMDAR and group I mGluRs activation have also been involved in the excessive synaptic loss observed during AD. Interestingly, the activation of extrasynaptic NMDAR (eNMDAR) induces the production of the S-nitrosylation of Cdk5, another factor implicated in AD excessive synaptic elimination. mGluR1: metabotropic glutamate receptor 1; sNMDAR: synaptic N-methyl-D-aspartate receptor; eNMDAR: extrasynaptic N-methyl-D-aspartate receptor; FMRP: fragile X mental retardation protein; oAβ: oligomeric amyloid β; CR3: complement receptor 3; ApoE4: Apolipoprotein E ε4; Cdk5: cyclin-dependent kinase 5. (A higher resolution / colour version of this figure is available in the electronic copy of the article).