2. Hippocampal synapses in ASD mouse models
The emergence of symptoms in individuals with ASD is not only linked to
a period of intense synaptic reshaping, but also coincides with critical
events in hippocampal development \cite{RN6}. Recent
years have witnessed the unveiling of ASD’s impact on hippocampal
synapses, with studies describing synaptic changes in both human samples
and mouse models \cite{RN39}. These modifications in
synaptic ultrastructure have been observed across various models and
different layers of the hippocampus. For instance, in the Fragile-X
model Fmr1 KO mice, hippocampal CA1 pyramidal cells exhibit an
increase in the density of dendritic spines with immature features,
including thin spines and macular PSDs \cite{RN46}.
Previous work has established perforated PSDs are enriched in glutamate
receptors (mGluRs), in contrast, macular PSDs are thought to mGluR-poor,
suggesting a direct link between PSDs morphology and size, and the
observed circuit connectivity in Fmr1 KO mice \cite{RN46}.
In the Mecp2+/- Rett’s syndrome model mice
there are decreases in dendritic spine density and dendritic swelling \cite{RN47}. On the level of hippocampal synaptic
transmission, the lack of functional MeCP2 resulted in reduced long-term
potentiation (LTP) and excitatory post-synaptic currents
(EPSCs) \cite{RN48}, whereas duplication of MeCP2 causes
enhanced LTP and EPSCs \cite{RN49,RN39}, an effect
likely a consequence of an increase or decrease in the number of
glutamatergic synapses respectively. A deficiency in MeCP2 also impacts
inhibitory synaptic transmission, leading to hyperexcitability of CA1
pyramidal neurons thought to originate from enhanced input from CA3
region, as evidenced through voltage-sensitive dye imaging \cite{RN39}. These findings suggest a disruption in the
E/I balance within the hippocampal circuit, originating from changes in
synaptic connectivity \cite{RN51,RN50,RN39}\cite{RN51,RN50,RN39}.
Similar features have also been observed in CA1 pyramidal neurons in
Shank models of ASD. In Shank3- deficient mouse models,
there is a decreased density of GluR1 puncta, associated with a decrease
in AMPA receptor levels at the synapses, indicating a deficit in synapse
maturation and a reduction in glutamatergic synaptic transmission
affecting CA1 connectivity \cite{RN52}. Shank1KO mice showed reduced PSD thickness and spine length in CA1 pyramidal
neurons leading to weakened synaptic transmission and suggesting a
reduction of the number of functional glutamatergic synapses \cite{RN53}. Shank2△e7-/- mice
also display reduced basal synaptic transmission in the hippocampus,
along with decreased EPSCs frequency, increased NMDA/AMPA ratio, and
enhanced LTP, alterations shown to be associated with an excess of
silent synapses, synapses lacking AMPA receptors, during development \cite{RN31}.
Mutations in neuroligins (NGL), primarily associated with non-syndromic
ASD and related behaviors, have undergone extensive examination within
the hippocampus \cite{RN25}. In the CA1 region, NGL3
mutation results in alterations in synaptic transmission at excitatory
synapses, particularly affecting AMPAR-mediated EPSCs \cite{RN25}. NGL3R451C model mice,
bearing a missense mutation in the coding region, leads to the retention
of NGL3 in the endoplasmic reticulum, reducing its synaptic expression
in CA1 and resulting in increased AMPAR-mediated excitatory synaptic
transmission and enhanced NMDAR-dependent LTP \cite{RN54,RN25}. Morphologically, the R451C mutation
increases the dendritic branching of CA1 pyramidal neurons in the
stratum radiatum, however synapse density remains unchanged. Changes are
also observed at the protein level, with higher concentrations of PSD-95
and SAP-102, two excitatory post-synaptic scaffolding proteins, as well
as an increase in the NR2B subunit of the NMDA receptor \cite{RN54}. Interestingly, during early post-natal
development, NGL3R451C mice exhibit an increased
frequency of Giant Depolarizing Potentials (GDPs), representing enhanced
GABAergic transmission, but no alterations in glutamatergic synaptic
transmission \cite{RN55}. In contrast,
NGL3R704C knock-in mice, bearing another neuroligin-3
mutation associated with ASD patients, demonstrate a reduced frequency
of mEPSCs linked to decreased AMPAR-mediated synaptic transmission, with
no changes in NMDA-mediated synaptic transmission. The R704C mutation
also affects glutamatergic receptor levels, evidenced by increased
levels of GluR1 and GluR3, although it does not impact synapse density
or size \cite{RN56}. The NGL3R704Cmutation truncates NGL3, increasing its interaction with AMPARs, leading
to enhanced endocytosis and reduced surface expression levels of the
receptor \cite{RN57}. Conversely, the same mutation
introduced into the related NGL4 isoform in cultured hippocampal neurons
yields opposite effects, increasing AMPAR and NMDAR-mediated synaptic
transmission. NGL4R704C neurons also exhibit increased
AMPAR levels at the surface, attributed to receptor stabilization rather
than internalization, as seen in the NGL3 mutation \cite{RN57}, emphasizing the mutation’s effect
specificity and the differential roles of the neuroligin isoforms. In
NGL4 KO mice, a decrease in GPH and GABAARγ 2, markers
of inhibitory synapses, is observed in the pyramidal layer of CA3,
although there are no changes in the number of inhibitory synapses or in
excitatory synaptic marker PSD95. These changes correlate with a
reduction in the amplitude and frequency of spontaneous IPSCs, leading
to perturbation of the γ-oscillations during behavioral tasks \cite{RN58}. Furthermore, CNTNAP2-null mutant mice,
lacking Caspr2, a neurexin-related cell-adhesion molecule, also show
altered synaptic function in the CA1 region. Notably, the amplitude of
IPSCs, especially from perisomatic inputs, is reduced, while the
frequency of spontaneous IPSCs is increased \cite{RN59,RN60}. This model also demonstrates a reduced density of PV+ interneurons
specifically in the CA1 region \cite{RN59}.
Mutation in the Scn1a and Scn2a genes, coding for the voltage-gated
sodium channel subunits Nav1.1 and Nav1.2, respectively, have been
linked to alteration in the neurotransmission \cite{RN61,RN62}. Specifically, the deletion of Nav1.1
channels in GABAergic interneurons within the hippocampal CA1 region
results in reduced sodium currents and lowered firing frequency of
GABAergic interneurons, decreasing inhibitory synaptic inputs.
Simultaneously, this deletion leads to an increase in excitatory
synaptic inputs due to a higher frequency of spontaneous EPSCs \cite{RN61}. On the contrary, the deletion of Nav1.2
channels in the CA1 region leads to a decrease in the frequency of
spontaneous EPSCs and suppress LTP \cite{RN62}.