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}.