BJPsych Advances (2018), vol. 24, 212–217 doi: 10.1192/bja.2017.27 ARTICLE Do patterns of synaptic pruning underlie psychoses, autism and ADHD?* Prasanna N. de Silva Prasanna N. de Silva is a consult- early adulthood (Box 1). Serial magnetic resonance SUMMARY ant psychiatrist specialising in old imaging (MRI) has revealed that these phases age psychiatry with Northumbria, This review of available longitudinal structural appear to be associated with grey matter volume Tyne and Wear NHS Foundation imaging and immunological findings in first-onset loss, which can be considered a proxy measure of Trust, working at Monkwearmouth schizophrenia, bipolar disorder, attention-deficit Hospital, Sunderland. She is also an the extent of pruning (Sowell 2001). hyperactivity disorder (ADHD) and autism sug- honorary senior lecturer at the Pruning is carried out by microglia performing University of Sunderland. gests that different patterns of synaptic pruning Correspondence Dr Prasanna N. de lead to various phenotypes. Proposals for future phagocytosis of unwanted synapses (Trapp 2007). Silva, Monkwearmouth Hospital, research strategies to try to replicate these find- However, to preserve other active circuits, synapses Newcastle Road, Sunderland SE5 ings are suggested, potential biomarkers to assist which are to be eliminated need to be ‘tagged’ with a 1NB, UK. Email: prasanna.desilva@ in diagnosis and determining the optimum duration protein marker. Studies in mice show that rapidly ntw.nhs.uk of maintenance treatment are considered and replicating neurons produce a signalling protein Copyright and usage ideas of potential immunotherapy augmentation called fractalkine, which binds to the receptor © The Royal College of Psychiatrists are outlined. CX3CR1, which is found exclusively in microglia, 2018 causing activation (Jones 2010). LEARNING OBJECTIVES Animal studies have shown that microglia can also • Understand the immunological basis of synaptic be activated in the prefrontal cortex by chronic stress *The original publication of this art- pruning icle included a spelling error in the • Comprehend the available research on longitu- (Wohleb 2012). The relationship between stress and title. This has been corrected. dinal brain imaging microglial activation is based on the release of cyto- • Be aware of future immunological therapeutic kines such as interleukin-6 (IL-6), induced by stres- strategies in psychosis, ADHD and autism sors. IL-6 penetrates the blood–brain barrier and activates microglia in the central nervous system DECLARATION OF INTEREST (Liu 2012). Furthermore, IL-6 plays a key role in None. pathogenesis of mood disorders. Microglial activity can be measured via positron emission tomography (PET) using radioactive ligands binding to benzodiazepine receptors (Banati It is estimated that over 50% of major psychiatric 2002). More recently, quantitative analysis of micro- conditions show prodromal symptoms in childhood glial activation has been achieved using the ligand and adolescence, when most synaptic pruning takes PK11195, another proxy measure of pruning (van place (Kim-Cohen 2003). Less than half of presenta- Berckel 2008). tions for these symptoms lead to diagnosis at the time, resulting in poor prospects as regards educa- tion, employment and relationships. Currently, there are no biomarkers to inform the specific diag- BOX 1 The three phases of synaptic pruning nosis or to guide treatment selection and duration. Phase 1 Initial generalised synaptic pruning between birth and 2 years Physiology of synaptic pruning Phase 2 Further generalised pruning during adolescence (11–15 years of age), with some variability between the Synaptic pruning plays a crucial role in brain matur- genders ation by reducing excessive amounts of synapses developed in utero (Chechik 1998). The process of Phase 3 The final spell of synaptic pruning is largely focused on the prefrontal area of the brain in early adult- pruning is activity dependent, using the principle hood (18–25 years of age) of ‘use it or lose it’. Pruning followed by myelination (Jetha & Segalowitz, 2012) to create more efficient circuits usually takes place during three age-related phases between birth and 212 BJPsych Advances (2018), vol. 24, 212–217 doi: 10.1192/bja.2017.27 Downloaded from https://www.cambridge.org/core. 25 Sep 2021 at 22:51:25, subject to the Cambridge Core terms of use. Patterns of synaptic pruning in psychoses, autism and ADHD Cells supporting neurons – astrocytes – also assist 6% of acute psychoses. Antibodies antagonising synaptic pruning by identifying synapses primed NMDA receptors can affect the hippocampus, for elimination (Chung 2013). Astrocytes secrete a causing hallucinations, paranoia and cognitive cytokine named transforming growth factor beta impairment (Mak 2009a). (TGF-β), which activates the complement cascade These syndromes are resistant to antipsychotics C1q, C4, C2 and finally C3 (Fishelson 2001; Banati but sensitive to steroids and other anti-inflammatory 2002), again leading to microglial activation. agents. Recurrences are common, but treatable with It is unclear why there are recurrent spells of immunotherapy, including plasmapheresis to clear pruning: whether onset is a threshold effect mediated the antibodies from circulation. Furthermore, there by synaptic load, or a response to social, hormonal or has been resurgence of interest in the association genetic signals. There appear to be variable amounts between increased risk of schizophrenia in later life of pruning in different parts of individual brains; and prenatal infections (Brown 2010), which can again the reason is unclear, but it is possibly asso- cause kindling of the fetal complement cascade via ciated with differential brain usage by individuals. the transfer of maternal IgG antibodies (Palmeria 2012). Early-onset psychiatric disorders: three syndromes Autism spectrum disorder Persisting, recurrent or brief psychotic illnesses in Autism spectrum disorder (ASD) presents in child- the absence of gross brain abnormality are called hood in around 1/150 children across the world, ‘functional’ psychoses (Murray 1997). Across the with a combination of inattention, sequencing diffi- world it is estimated that 1% of the adult population culty and behavioural patterns that appear to be experience these syndromes. These include schizo- present to cope with difficulty in establishing and phrenia, bipolar disorder and a ‘hybrid’ psychosis maintaining social communication and emotional called schizoaffective disorders, which is a mixture closeness to others (Chawarska 2007). Often there of symptoms seen in schizophrenia and bipolar dis- are behavioural rituals which, if prevented, can order. These disorders usually show ‘prodromal’ result in a display of severe anxiety. ASD is also features in adolescence such as attentional and associated with various compulsive disorders, includ- memory difficulties, as well as sequencing problems ing self-harming, obsessional checking and and affective changes or apathy. The onset of acute vocalisations. symptoms such as mania, delusions and hallucina- tions generally occur in early adulthood, often in Attention-deficit hyperactivity disorder the context of major life changes or substance Attention-deficit hyperactivity disorder (ADHD) misuse. It is also not uncommon for individuals (Kooij 2010), which affects 3–5% of children across with psychoses to have experienced severe stress the world, is a condition with inattention and sequen- (for example sexual abuse) in childhood, which is cing problems. Boys tend to show more hyperactive known to heighten immune responsivity (Ayaydin features, with girls showing more inattention. There 2016). is a tendency to display risky behaviours as part of impulsivity. Psychoses A model of how immune processes can cause Evidence of pruning in psychoses psychosis has emerged via encephalitic conditions Thompson and colleagues (2001) serially scanned the presenting with psychosis in which antibodies to brains of young adolescents with schizophrenia, N-methyl-D-aspartate (NMDA) receptors or voltage- alongside their healthy siblings and matched controls, gated potassium channels have been present (Shah over a 5-year period. They found a fourfold excess of 2013). Immune processes appear to explain around permanent grey matter loss in the children with schizophrenia compared with controls. There was also evidence of excess grey matter loss in siblings, BOX 2 Complement cascade which subsequently ameliorated (Mattai 2011). Furthermore, a recent PET study found excess micro- The complement cascade is a biochemical process involv- glial activity in people with schizophrenia and, to a ing the C1 to C9 complement proteins in which one protein lesser extent, in people at high risk of the disease com- interacts with another in a specific sequence. C5b with C6, pared with controls (Bloomfield 2015). C7, C8, and C9 form the membrane attack complex that Immunological research in schizophrenia has initiates cell lysis. Other molecules, such as C3a and C5a, shown that the complement cascade is altered, act as cytokines, leading to inflammation. with C1, C3 and C4 showing increased mean activity in people with schizophrenia, whereas C2 shows BJPsych Advances (2018), vol. 24, 212–217 doi: 10.1192/bja.2017.27 213 Downloaded from https://www.cambridge.org/core. 25 Sep 2021 at 22:51:25, subject to the Cambridge Core terms of use. de Silva reduced activity (Hakobyan 2005). A further study dysregulation, i.e. there is excess dopamine supply