Dissociable effects of complement C3 and C3aR on survival and morphology of adult born hippocampal neurons, pattern separation, and cognitive flexibility in male mice

Abstract

1. Dis s o ci a bl e eff e c t s of c o m pl e m e n t C 3 a n d C 3 a R o n s u rviv al a n d m o r p h olo gy of a d ul t b o r n hi p p o c a m p al n e u r o n s , p a t t e r n s e p a r a tio n, a n d c o g ni tiv e flexibility in m a l e mi c e. B r ai n, Be h a vior, a n d I m m u ni ty 9 8 , p p . 1 3 6-1 5 0.

Complement activation and increased anaphylatoxin receptor expression are associated with cortical grey matter lesions and the compartmentalised inflammatory response of multiple sclerosis

“…It is important to note that complement can elicit a range of protective as well as damaging responses in the CNS. For example, C3a/C3aR1 and C5a/C5aR1 axis activation is reported to protect cultured neurons from excitotoxic death ( van Beek et al, 2001 ; Mukherjee et al, 2008 ) and is associated with the induced release of neurotrophins, cell survival and enhanced neurogenesis, in some settings ( Jauneau et al, 2006 ; Haynes et al, 2013 ; Westacott et al, 2021 ); whilst C3a and C5a overexpressing mice displayed similar rates of remyelination ( Ingersoll et al, 2010 ), although presenting larger and more inflammatory demyelinating lesions. More work clearly needs to be done to fully understand the role of C3aR1 and C5aR1 activation at all stages of MS. A third receptor C5aR2 (C5L2 or GPR77), is less well characterised and regarded as a scavenger or default receptor competing with C5aR for C5a binding.…”

Complement Dependent Synaptic Reorganisation During Critical Periods of Brain Development and Risk for Psychiatric Disorder

“…Microglia also induce apoptosis and engulf adult born stem cells in the dentate gyrus neurogenic niche (Sierra et al, 2010). Our own data has shown that deficient C3 signalling leads to greater survival of adult born hippocampal stem cells (Westacott et al, 2021) but whether this phenotype is related to potentially altered microglial-apoptosis coupled phagocytosis has not been investigated.…”

“…Emerging evidence implicates physiological roles of complement in multiple aspects of neurodevelopment (reviewed in Coulthard et al, 2018a) including embryonic neurogenesis (Hawksworth et al, 2014;Coulthard et al, 2017Coulthard et al, , 2018b, neuronal precursor migration (Gorelik et al, 2017), neurite extension and neuronal morphology (Shinjyo et al, 2009;Moriyama et al, 2011;Lian et al, 2015), regulation of several stages of adult neurogenesis (Rahpeymai et al, 2006;Moriyama et al, 2011;Westacott et al, 2021), synaptogenesis (Stokowska et al, 2017) and learning and memory (Perez-Alcazar et al, 2013;Shi et al, 2015;Wang et al, 2020;Westacott et al, 2021). These processes likely have the potential to influence synaptic strength, plasticity and thus pruning.…”

“…Interfering with C3, or disrupting opsonins that tag synapses, such as C1q or C3b, would likely create significant vulnerability to bacterial or viral infections. In addition, the possibility of disturbing ongoing homeostatic functions of complement in the adult brain such as regulating adult neurogenesis and synaptic plasticity (Wang et al, 2020;Westacott et al, 2021) have to be considered. However, if as recent studies suggest, complement can contribute but is not necessary for synaptic pruning in the healthy brain (Sager et al, 2021;Yilmaz et al, 2021), then targeted therapies to reduce high C4A levels in carriers of risk-associated variants (Sekar et al, 2016) might be effective without disrupting the normal underlying synaptic pruning processes.…”

“…In addition, greater amygdalar, hippocampal and cortical volumes have been reported in ASD (Schumann et al, 2004;Hutsler and Zhang, 2010) and these regions display altered developmental trajectories compared to typical development (Schumann et al, 2004). There is also evidence that the complement system can impact on fear and anxiety behaviour (Westacott et al, 2022) as well as cognition (Westacott et al, 2021) and mood (Crider et al, 2018), psychological domains frequently perturbed in psychiatric disorders. This raises the fundamental question of whether complement-dependent synaptic pruning in brain areas subserving these functions may contribute to clinical presentation and symptomatology in psychosis and other psychiatric disorders.…”