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Page 8 Heinzer et al. J Transl Genet Genom 2024;8:1-12 https://dx.doi.org/10.20517/jtgg.2023.39

[61]
reduction in the probability of glutamate release from presynaptic terminals . Changes in the short-term
+/-
plasticity of Setd1a mice have been elucidated through observation of increases in short-term
[17]
depression . These observations suggest that the observed alteration of signalling processes and synaptic
[17]
plasticity in these haploinsufficiency mouse models may be contributing factors to cognitive symptoms .
Overall, these findings relating to SETD1A suggest that schizophrenia risk may be mediated by abnormal
[57]
synaptic development and function, arising as a result of aberrant epigenetic modifications .
UBIQUITIN-PROTEASOME SYSTEM IMPAIRMENT
The ubiquitin-proteasome system (UPS) plays a fundamental role in neuronal homeostasis via protein
degradation . Localised at synapses, the UPS has been implicated in synaptic development, maintenance,
[26]
and plasticity. Given these implications, dysfunction of this degradation system has been related to various
neurological disorders . Components of the UPS are found to be mis-regulated in numerous diseases and
[26]
E3 ligases may be of particular interest given their role in specifying ubiquitination targets for
degradation . The schizophrenia risk genes HERC1, CUL1, and AKAP11 all have a role in the UPS.
[62]

The tambaleante (tbl) mutant mouse is an extensively characterised model organism that carries a
spontaneous mutation in the HERC1 E3 ubiquitin ligase [26,63] . The tbl mouse was first described as a model
of adult cerebellar ataxia, which is caused by Purkinje neuron death in the cerebellum . NMDARs and
[38]
[21]
GABA neurotransmitters are essential in Purkinje neuron development . Cerebellum-related spatial
learning alterations are observed in tbl mutant mice, as well as impairments in hippocampal learning and
memory . In addition to having a profound impact on the growth and maintenance of the cerebellar and
[38]
hippocampal structures, Herc1 has also been implicated in the amygdala through tbl mouse studies . The
[63]
[63]
amygdala plays a crucial role in associative learning, which is impaired in tbl mice . These learning deficits
are associated with a lower density of glutamatergic synaptic vesicles in the lateral amygdala and
hippocampus of tbl mice [39,63] . These glutamatergic synapses are a component of dendritic spines. E3 ligases
of the UPS have previously been implicated in the maintenance of the size and density of such spines on
neurons of the lateral amygdala . These results collectively suggest that HERC1 E3 ubiquitin ligase may
[63]
play a role in the regulation of postsynaptic dendritic spinogenesis and the maintenance of homeostasis
within presynaptic terminals .
[63]
As noted previously, CUL1 is an invariable component of the SCF E3 ubiquitin ligases. Few genetic models
exist that have specifically investigated CUL1, but models exploring overall SCF complex alterations are
available. It has been shown in mice that engineered ubiquitin variants that target the Cul1 binding site
[62]
work to inhibit SCF ubiquitin ligases . However, no investigation into behavioural phenotypes or brain-
related morphological and functional defects was undertaken in this study. Total knockout of F-box protein
Fbxw7 in mice induces alterations of the overall SCF complex, manifesting in vascular development
abnormalities in the brain and ultimately causing embryonic lethality . FBXW7 is a well-characterised
[25]
variant of the F-box protein, the variable component of the SCF complex, and has been implicated in
neurodevelopment and neurodegeneration . Despite the current lack of brain-specific investigations
[27]
focussed on CUL1, results from the existing studies suggest that alterations in the SCF complex may have
implications for neurodevelopment and neurological functions.

A recent study investigating FBXW7 implicated AKAP11 as a target of SCF complex-mediated degradation.
The FBXW7 component of the SCF complex binds to target substrates via a phosphodegron consensus
motif and is found on proteins targeted by the UPS for proteasomal degradation . Such FBXW7-binding
[25]
phosphodegrons were located on AKAP11 proteins, suggesting that the SCF complex E3 ligase may be
involved in maintaining levels of this neuronal synapse plasticity regulator [12,64] .