SYNGAP1 haploinsufficiency is one of the most common monogenic causes of
nonsyndromic moderate to severe intellectual disability (NSID) and autism (Hamdan
et al., 2009; Pinto et al., 2010). De novo truncating or frameshift mutations in the
SYNGAP1 gene lead to the loss of the encoded protein Synaptic GTPase activating
protein (SynGAP), one of the most abundant of postsynaptic proteins (Hamdan et al.,
2011). SynGAP, present at excitatory and inhibitory synapses (Kim et al., 1998), acts
as a key regulator of highly conserved signaling pathways linked to AMPA- and
NMDA-receptor dependent plasticity at the post synaptic density (Krapivisky et al.,
2004; Vazquez et al., 2004).
The Syngap mouse model has been extensively used to understand the
pathophysiology underlying abnormal SynGAP-mediated signaling. Syngap
heterozygous (het) mice demonstrate a range of physiological and behavioural
abnormalities from development to adulthood (Komiyama et al., 2002; Muhia et al.,
2010). However, recent advances in techniques for genome manipulation have allowed
for the generation of rat models of neurodevelopmental disorders, including Syngap;
enabling phenotypes to be validated across species and to address cognitive and social
dysfunction, using paradigms that are more difficult to assess in mice.
In this study, we examined the pathophysiology associated with a heterozygous
deletion of the C2 and catalytic GAP domain of the protein, in Long-Evans rats (het).
In contrast with het mice, het rats do not present with hyperactivity and can be
habituated to an open field environment. To examine associative recognition memory,
we tested the rats in five spontaneous exploration tasks for short-term and long-term
memory, object-recognition (OR), object-location (OL), object-place (OP), object-context
(OC) and object-place-context (OPC). Both groups were able to perform short-term
memory tasks, but only wild type rats performed above chance in OL with a
24hour delay, suggesting deficits in long- term spatial memory. We also tested if
partial loss of the GAP domain in SynGAP affects social behaviour in rats and we
found that het rats exhibited impaired short- term social memory, with no signs of
social isolation. These findings do not fully recapitulate previous abnormalities
reported in the mouse model of SYNGAP1 haploinsufficiency, suggesting that some
key behavioural phenotypes may be species-specific.
Furthermore, based on physiological deficits that Syngap het mice exhibit, such as
alterations in mEPSC/mIPSC amplitude and frequency and evoked cortical
hyperexcitability in vitro (Guo et al., 2009; Ozkan et al., 2014), we also aimed to test
if in vivo neuronal activity and circuit properties are altered. Using two-photon calcium
imaging in awake mice, we focused on two areas of the cortex; a primary sensory area,
the binocular region of the visual cortex (V1), and an association area, the medial
posterior parietal cortex (PPC). Both areas have been found to maintain activity during
visual discrimination tasks but to present with divergent activity trajectories (Harvey
et al., 2012; Goard et al., 2016). We found preliminary evidence that neurons in layer
2-3 of the PPC of Syngap mice are hypoactive in basal conditions when animals are
still in the dark, compared to wild type controls. When we assessed whether that
changes when animals are running, we found that during locomotion neurons of both
genotypes increase their activity, consistent with previous findings in wild type mice
(McGinley et al., 2015; Pakan et al., 2016). However, this response gain is exaggerated
in Syngap het neurons of the PPC. In contrast to above findings in PPC, results in V1
show that layer 2-3 neurons are hyperactive during both behavioural states, suggesting
seemingly different computations of these two cortical areas.
This work provides the first evidence for a dysregulated neuronal circuit in vivo in both
visual and parietal cortex of Syngap mice, two areas critical for sensory processing
that has been found to be affected in individuals with NSID and autism (Joosten and
Bundy, 2010). We also provide first evidence of the effect of loss of SynGAP activity
in behaviour of rats, complimenting existing data in the literature in a species-specific
manner and providing greater insight into sensory and cognitive dysfunction
associated with dysregulation in SynGAP-mediated signaling