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Ellis Chika Profile
Ellis Chika

@_ecologos

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NIHR Academic Clinical Fellow @QMULPsychiatry | brain imaging researcher @MRC_LMS @ImperialMed @KingsIoPPN | Trainee Psychiatrist @NHS_ELFT

Joined May 2020
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@_ecologos
Ellis Chika
2 years
I'm pleased to share our review of the synaptic hypothesis of schizophrenia, out now in @molpsychiatry, with Oliver Howes,.@MRC_LMS @KingsIoPPN @QMUL_WIPH.We reflect on >4 decades of evidence, and use this to propose an updated synaptic hypothesis.
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@_ecologos
Ellis Chika
2 years
RT @sameerjauhar: Out in Translational Psychiatry , we examine the relationship between 2 of the major players thou….
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@_ecologos
Ellis Chika
2 years
RT @VernonLab_KCL: Curious about hiPSC to study psychiatric disorders? Check our consensus paper from the ECNP iPS….
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@_ecologos
Ellis Chika
2 years
Some unanswered questions:. Are synaptic alterations present in unmedicated first-episode, and clinical high-risk?. Are there post-synaptic deficits in vivo?. Does synaptic profile differ across distinct clinical sub-types?. Are synaptic and dopaminergic markers linked in vivo?.
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@_ecologos
Ellis Chika
2 years
➡️Genetic variants render synapses vulnerable to pruning. ➡️Stress/immune activation causes ⬆️pruning by glia. ➡️This causes EI imbalance, so cog+neg symptoms; and disinhibited projections to striatum, so hyperdopaminergia, so psychosis. ➡️Stress of psychosis causes more pruning.
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@_ecologos
Ellis Chika
2 years
With these lines of evidence, we can provide a further update to the synaptic hypothesis of schizophrenia (version III)
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@_ecologos
Ellis Chika
2 years
We do not find the normal association between synaptic density and glutamate in schizophrenia. This suggests a loss of glutamatergic synapses and/or lower glutamatergic-to-GABAergic synapse ratio, potentially contributing to observed EI imbalance.
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@_ecologos
Ellis Chika
2 years
In [11C]UCB-J PET, we now have a tool to measure a marker of synaptic density in the living human brain. We find evidence for reduced synaptic density in both cortical and subcortical regions in schizophrenia compared to controls:.
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@_ecologos
Ellis Chika
2 years
Synaptic changes may underlie imaging findings. In preclinical studies, stress is linked to reduced grey matter volume, dendritic volume and spine density. And dendritic volume loss and MRI-estimated grey matter volume loss are strongly associated (R2>0.9).
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@_ecologos
Ellis Chika
2 years
Meta-analyses of neuroimaging studies indicate lower cortical grey matter volumes and lower/unaltered subcortical volumes in schizophrenia, from first episode. Clinical high risk for schizophrenia subjects show similar patterns of lower grey matter volumes and cortical thinning.
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@_ecologos
Ellis Chika
2 years
Human iPSC-derived neurons show lower SV2 and synapsin I puncta density, vesicle release, PSD-95 protein levels and dendritic spine density in schizophrenia, and elevated, complement-dependent elimination of synaptic structures. Key work by @SellgrenLab ➡️
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@_ecologos
Ellis Chika
2 years
Post-mortem studies of schizophrenia show lower levels of markers of both pre- and post-synaptic elements in patients, particularly affecting cortical brain regions. See key meta-analysis of pre-synaptic markers by @eosimo.
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@_ecologos
Ellis Chika
2 years
In schizophrenia, genetic association studies point to alterations in genes involved in synaptic organisation, differentiation, transmission, and signalling, and complement expression 🧬. In preclinical studies, maternal infection 🫄🏿+ stress 😮‍💨 alter synaptic development.
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@_ecologos
Ellis Chika
2 years
A feature of neurodevelopment is the elimination of inactive synapses by glia. These are tagged by complement protein C1q, which triggers a cascade leading to the phagocytosis of synapses by glia
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Ellis Chika
2 years
Human postmortem studies indicate that synaptic density peaks in early childhood, followed by intermediate levels in adolescence and early adulthood, and lower but stable levels in the remaining adulthood
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@_ecologos
Ellis Chika
2 years
Since versions I and II, methodological advances have produced a step-change in the available evidence. So now we can consider the evidence for a mechanism for faulty synaptic elimination in schizophrenia, and how this is linked to genetic or environmental risk factors.
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@_ecologos
Ellis Chika
2 years
Crucially, they added spatial specificity, proposing excessive cortical synaptic pruning and insufficient subcortical pruning in schizophrenia, given new neuroimaging evidence for altered brain volumes (CT, MRI) and frontal hypometabolism (PET, SPECT, 31P-MRS, 133Xe inhalation).
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@_ecologos
Ellis Chika
2 years
In 1994, Keshavan, Anderson and Pettegrew produced the 2nd major version of the synaptic hypothesis
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@_ecologos
Ellis Chika
2 years
So, maybe an error in developmental synaptic loss leads to schizophrenia. But much of the supporting evidence was indirect.
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@_ecologos
Ellis Chika
2 years
Feinberg noted that potential markers of synaptic function (e.g. EEG wave amplitude, brain metabolic rate) were altered in schizophrenia, and the illness typically emerges during a developmental time window involving extensive synaptic loss (late adolescence/early adulthood).
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@_ecologos
Ellis Chika
2 years
In 1982, Irwin Feinberg proposed arguably the 1st synaptic hypothesis of schizophrenia, arguing that the illness is caused by a loss of synaptic density
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