Due to the indicative synaptic elimination as a core phenomenon co-occurring or predicating schizophreniform pathogenesis and the temporal comorbidity of anomalous self-experience, we posit that the neurobiological etiology of formal thought disorder in schizophrenia arises from robust loss of synaptic density at young adulthood mediated by dysregulation of Rho GTPase proteins marked by overzealous targeting from the innate immune system complement cascade.

1. Synaptic Elimination Causes Anomalous Self Experience in Schizophrenia
Alec Hoyland, Avital Rodal
Dept. of Biology, Brandeis University, Waltham, MA 02454
Introduction
Schizophrenia is a severe, chronic neuropsychiatric disorder affecting
1% of the world population characterized by psychosis,
neurocognitive deficits, and negative symptoms ranging from
anhedonia, flat affect, and asocial behavior. Schizophrenia typically
onsets during young adulthood, following a prodromal period of
subacute cognitive deficits and negative symptoms, characterized by
a psychotic break (Tandon et al. 2009). Neuroimaging and
neuroanatomical studies have correlated reductions in synaptic
density in the prefrontal cortex and temporal lobes with onset of the
prodromal period (Faludi and Mirnics 2011; Boksa 2012)
Anomalous Self-Experience
Anomalous self-experiences (self-
disorders) have also been identified as
unique to schizophrenia among
psychotic disorders. They onset during
the prodromal period of the disorder
and are associated with pre-psychotic
schizotypy (Parnas and Handest 2003;
Huang 2012, Öngür et al. 2010). There
is a direct correlation between the
severity of prodromal psychosis as rated
symptomatically and anomalous self-
experience (Brent et al. 2014; Koren et
al. 2013).
Biological Basis of Synaptic Elimination
C4 alleles of the major histocompatibility complex (MHC) are highly
correlated with schizophrenia. In mouse models, C4 promoted
synapse elimination in temporally localized neurodevelopment of a
neuronal circuit. The late phase of cortical maturation in humans
corresponds to the same period of prodromal and first-episode
schizophrenia (Sekar et al. 2016).
Fig. 6. The MHC is strongly correlated with schizophrenia (Sekar 2016)
Future Directions
1. Knockdown of Rho GTPase CDC42 in macaques and mice. If
knockdown of CDC42 is a primary risk factor in schizophrenia, we
should see schizophreniform symptomatology.
2. Application of the antifungal/immunosuppressant drug rapamycin
to macaques and mice. Rapamycin has been shown to increase
synaptic pruning in Ts2+/mice by stimulating the innate immune
system. We should expect to see animals develop
ASE/schizophreniform symptomatology at young adulthood.
3. Upregulation of complement cascade complex in animal models
should lead to increased synaptic pruning and ASE/schizophreniform
symptomatology.
We anticipate these experiments to provide evidence for a
neuroimmune model of schizophrenia mediated by synaptic
pruning.
Synaptic Elimination
Rho GTPase regulatory proteins direct synapse development and
plasticity by controlling the spatio-temporal regulation and signaling
specificity of Rho GTPases (Tolias et al. 2011). Glutamine/glutamate
(Glx) and N-acetylaspartate (NAA) levels in the dorsolateral
prefrontal cortex were found to be elevated in young adulthood
among attenuated and first-episode psychotics (schizophrenia
spectrum) (Boksa 2012, Liemburg 2016).
Fig. 3. Modeling
schizophreniform pathogenesis
(Parnas 2013)
Fig. 2. Abnormalities in neural
activity in schizophrenia
The schizophrenic brain
experiences abnormal activation
in the medial prefrontal cortex
(Öngür et al. 2010)
(Parnas 2013)
Fig. 5. Linear regression of metabolite levels with age, (a) Glx and (b)
NAA in patients (○) and (c) Glx and (d) NAA in UHR (□; dashed lines)
compared to their control groups (• and ■ resp., solid lines)
(Liemburg 2016)
Fig. 4. Audioradiogram optical density,
horizontal bars indicate mean (Hill et al. 2006)
Conclusion
Due to the indicative synaptic elimination as a core phenomenon
co-occurring or predicating schizophreniform pathogenesis and the
temporal comorbidity of anomalous self-experience, we posit that
the neurobiological etiology of formal thought disorder in
schizophrenia arises from robust loss of synaptic density at young
adulthood mediated by dysregulation of Rho GTPase proteins
marked by overzealous targeting from the innate immune system
complement cascade.
Citations
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Acknowledgements
We would like to acknowledge Adriane Otopalik and Ellen Wright.