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

We now know that the immune system plays a major role in the complex processes underlying brain development throughout the lifespan, carrying out a number of important homeostatic functions under physiological conditions in the absence of pathological inflammation or infection. In particular, complement-mediated synaptic pruning during critical periods of early life may play a key role in shaping brain development and subsequent risk for psychopathology, including neurodevelopmental disorders such as schizophrenia and autism spectrum disorders. However, these disorders vary greatly in their onset, disease course, and prevalence amongst sexes suggesting complex interactions between the immune system, sex and the unique developmental trajectories of circuitries underlying different brain functions which are yet to be fully understood. Perturbations of homeostatic neuroimmune interactions during different critical periods in which regional circuits mature may have a plethora of long-term consequences for psychiatric phenotypes, but at present there is a gap in our understanding of how these mechanisms may impact on the structural and functional changes occurring in the brain at different developmental stages. In this article we will consider the latest developments in the field of complement mediated synaptic pruning where our understanding is beginning to move beyond the visual system where this process was first described, to brain areas and developmental periods of potential relevance to psychiatric disorders.

Complement C3 and C3aR mediate different aspects of emotional behaviours; relevance to risk for psychiatric disorder.

Complement is a key component of the immune system with roles in inflammation and host-defence. Here we reveal novel functions of complement pathways impacting on emotional reactivity of potential relevance to the emerging links between complement and risk for psychiatric disorder. We used mouse models to assess the effects of manipulating components of the complement system on emotionality. Mice lacking the complement C3a Receptor (C3aR-/-) demonstrated a selective increase in unconditioned (innate) anxiety whilst mice deficient in the central complement component C3 (C3-/-) showed a selective increase in conditioned (learned) fear. The dissociable behavioural phenotypes were linked to different signalling mechanisms. Effects on innate anxiety were independent of C3a, the canonical ligand for C3aR, consistent with the existence of an alternative ligand mediating innate anxiety, whereas effects on learned fear were due to loss of iC3b/CR3 signalling. Our findings show that specific elements of the complement system and associated signalling pathways contribute differentially to heightened states of anxiety and fear commonly seen in psychopathology.

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

Adult hippocampal neurogenesis (AHN) is a form of ongoing plasticity in the brain that supports specific aspects of cognition. Disruptions in AHN have been observed in neuropsychiatric conditions presenting with inflammatory components and are associated with impairments in cognition and mood. Recent evidence highlights important roles of the complement system in synaptic plasticity and neurogenesis during neurodevelopment and in acute learning and memory processes. In this work we investigated the impact of the complement C3/C3aR pathway on AHN and its functional implications for AHN-related behaviours. In C3-/- mice, we found increased numbers and accelerated migration of adult born granule cells, indicating that absence of C3 leads to abnormal survival and distribution of adult born neurons. Loss of either C3 or C3aR affected the morphology of immature neurons, reducing morphological complexity, though these effects were more pronounced in the absence of C3aR. We assessed functional impacts of the cellular phenotypes in an operant spatial discrimination task that assayed AHN sensitive behaviours. Again, we observed differences in the effects of manipulating C3 or C3aR, in that whilst C3aR-/- mice showed evidence of enhanced pattern separation abilities, C3-/- mice instead demonstrated impaired behavioural flexibility. Our findings show that C3 and C3aR manipulation have distinct effects on AHN that impact at different stages in the development and maturation of newly born neurons, and that the dissociable cellular phenotypes are associated with specific alterations in AHN-related behaviours.

Haploinsufficiency of the schizophrenia and autism risk gene Cyfip1 causes abnormal postnatal hippocampal neurogenesis through microglial and Arp2/3 mediated actin dependent mechanisms.

Genetic risk factors can significantly increase chances of developing psychiatric disorders, but the underlying biological processes through which this risk is effected remain largely unknown. Here we show that haploinsufficiency of Cyfip1, a candidate risk gene present in the pathogenic 15q11.2(BP1-BP2) deletion may impact on psychopathology via abnormalities in cell survival and migration of newborn neurons during postnatal hippocampal neurogenesis. We demonstrate that haploinsufficiency of Cyfip1 leads to increased numbers of adult-born hippocampal neurons due to reduced apoptosis, without altering proliferation. We show this is due to a cell autonomous failure of microglia to induce apoptosis through the secretion of the appropriate factors, a previously undescribed mechanism. Furthermore, we show an abnormal migration of adult-born neurons due to altered Arp2/3 mediated actin dynamics. Together, our findings throw new light on how the genetic risk candidate Cyfip1 may influence the hippocampus, a brain region with strong evidence for involvement in psychopathology.