Understanding Autism Spectrum Disorder using Syngap1 heterozygous mutant mice as a model
A cardinal feature of human brain development is that
sensory, cognitive, and emotional experiences shape synapses
and neural-circuit development. Neuronal activity triggers
changes at the synapse, altering the composition, shape and
strength of the synapse. These neuronal activity-dependent
modifications are necessary for learning and memory and
various behavioural responses, particularly during
development. Several studies have shown that these features
are disrupted in Intellectual Disability (ID) and Autism
Spectrum Disorder (ASD), which affects ~3-4% of the
population in the world. Mutations that cause ID and ASD are
increasingly found in genes that encode proteins that
regulate synaptic function and structure. De novo
heterozygous (het) mutations in the gene that encodes for
synaptic RASGAP, SYNGAP1, has been shown to cause ID and
increase the risk for developing ASD in young children. It
has been demonstrated that, in Syngap1 heterozygous
mutant (Het) mice, the net effect of a heterozygous mutation
in Syngap1 was to unleash dendritic spine synapse in
the neonatal hippocampus during development, which drives
excitatory/inhibitory (E/I) imbalance, seizures and various
behavioural deficits. This early dendritic synaptic spine
maturation is also linked to the altered duration of the
critical period of plasticity that leads to life-long
cognitive and social deficits.
Image 1: Whole-cell patch-clamp of a mouse CA1 pyramidal cell