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Heinzer et al. J Transl Genet Genom 2024;8:1-12 https://dx.doi.org/10.20517/jtgg.2023.39 Page 7

In wild-type rodents, repeated METH administration induces NMDAR dysfunction and leads to a
[56]
reduction in Grin2a expression . Likewise, anti-NMDAR autoantibody encephalitis can produce
[34]
symptoms resembling those observed in schizophrenia . These autoantibodies cause receptor
[34]
internalisation from the plasma membrane of neurons, resulting in NMDAR hypofunction . In
experimental mouse models, both PCP and anti-NMDAR autoantibodies induce NMDAR hypofunction in
[34]
excitatory neurons and elicit schizophrenia-like symptoms, including memory deficits .
The Sp4 hypomorphic mouse is a further valuable model that aids our understanding of the putative
[43]
NMDAR-specific hypoglutamatergic function underlying schizophrenia . The mouse Sp4 gene is
expressed abundantly in the hippocampal CA1 region. Relative to wild-type mice, Sp4 hypomorphic mice
display impaired LTP in the hippocampal CA1 and impaired spatial learning and memory, which mimic
[43]
cognitive deficits seen in schizophrenia . Following the publication of the SCHEMA results and
confirmation of SP4 as a schizophrenia risk gene, further investigations into Sp4 hypomorphic mice were
[44]
conducted . The hippocampal vacuolisation observed in these mice with reduced Sp4 expression was
found to be associated with the deficits in LTP as well as the observed sensorimotor gating, learning, and
memory deficits [44,57] .

GRIA3 codes for GluA3, an AMPAR subunit, and dysfunction of AMPARs has also been implicated in
schizophrenia aetiology, although this has been less extensively investigated. Knockout models of this gene
in mice have been established and studied, yielding results that show impairment in excitatory
neurotransmission in the medial prefrontal cortex (mPFC) and reduced neuronal activity . In mice,
[58]
heterozygous deletion of Gria3 was associated with aggressive behaviour, which could be alleviated by the
injection of an adeno-associated virus vector expressing GluA3 into the mPFC .
[58]

CHROMATIN MODIFICATION
With the discovery of rare LOF variants in SETD1A conferring a large increase in risk for schizophrenia,
epigenetic dysregulation gained attention as an important mechanism in the pathogenesis of the disorder .
[8]
The Setd1a haploinsufficiency mouse model (Setd1a ) has been investigated extensively in order to throw
+/-
light on the epigenetic mechanisms presumed to be involved in schizophrenia pathophysiology .
[59]
Setd1a mice have been shown to have approximately a 50% decrease in Setd1a protein in frontal brain
+/-
+/-
[60]
regions . The effects of this haploinsufficiency in the mPFC and striatum of the Setd1a mice were also
investigated, yielding valuable results . Single-cell RNA sequencing revealed that the H3K4me3-dependent
[59]
transcriptional function of Setd1a differed between cell types and neuronal subtypes in these brain
[59]
regions . In the mPFC, the decrease in H3K4me3 correlated with a decrease in gene expression in
excitatory neurons, particularly in Foxp neurons . In these mPFC-localised neurons, morphological
2+
[59]
defects including dendrite morphology defects and exocytosis impairment have been observed [59-61] . In
addition, schizophrenia-like behavioural phenotypes, including impaired sociality, sensorimotor gating
+/-
defects, and deficits in working memory, were observed in these Setd1a mice [59-61] . However, there are
some discrepancies between the behavioural phenotypes observed in Setd1a mice as part of the different
+/-
studies that have been conducted, which may be attributable to differing genetic backgrounds or behaviour-
testing protocols .
[59]
Investigations into the Setd1a haploinsufficiency mouse model have also revealed an involvement of Setd1a
+/-
in excitatory synaptic plasticity. In the mPFC of Setd1a mice, excitatory synaptic transmission was
observed to be attenuated in layer 2 and 3 (L2/3) pyramidal neurons (PNs) . While postsynaptic SETD1A
[61]
is crucial for the functionality of excitatory synapses, the reduction of Setd1a in L2/3 PNs further caused a