Syngap1 Haploinsufficiency Damages a Postnatal Critical Period of Pyramidal Cell Structural Maturation Linked to Cortical Circuit Assembly

Abstract

Background Genetic haploinsufficiency of Syngap1 commonly occurs in developmental brain disorders, such as intellectual disability (ID), epilepsy, schizophrenia (SCZ), and autism spectrum (ASD) disorder. Thus, studying mouse models of Syngap1 haploinsufficiency may uncover pathological developmental processes common among distinct brain disorders. Methods A Syngap1 haploinsufficiency model was used to explore the relationship between critical period dendritic spine damage, cortical circuit assembly and the window for genetic rescue in order to understand how damaging mutations disrupt key substrates of mouse brain development. Results Syngap1 mutations broadly disrupted a developmentally sensitive period that corresponded to the period of heightened postnatal cortical synaptogenesis. Pathogenic Syngap1 mutations caused a coordinated acceleration of dendrite elongation and spine morphogenesis, and pruning of these structures in neonatal cortical pyramidal neurons. These mutations also prevented a form of developmental structural plasticity associated with experience-dependent reorganization of brain circuits. Consistent with these findings, Syngap1 mutant mice displayed an altered pattern of long-distance synaptic inputs into a cortical area important for cognition. Interestingly, the ability to genetically improve the behavioral endophenotype of Syngap1 mice decreased slowly over postnatal development and mapped onto the developmental period of coordinated dendritic insults. Conclusions Pathogenic Syngap1 mutations have a profound impact on the dynamics and structural integrity of pyramidal cell postsynaptic structures known to guide the de novo wiring of nascent cortical circuits. These findings support the idea that disrupted critical periods of dendritic growth and spine plasticity may be a common pathological process in developmental brain disorders.

Genetic and neurodevelopmental spectrum ofSYNGAP1-associated intellectual disability and epilepsy

“…ASD as well other neurodevelopmental disorders could in many cases result from the interruption or impairment of the maturation processes of neuronal networks that are driven by neuronal activity during a critical period of brain development 39. This scenario is particularly relevant to the fact that the clinical and morphological consequences of SYNGAP1 haploinsufficiency in mice, that is, behavioural disturbances and premature dendrite elongation, are restricted to gene disruption during a given period of brain development 4 9. Following this hypothesis, SYNGAP1 encephalopathy may be regarded as an example of premature closing of the time window for cognitive development in humans.…”

“…Syngap1 haploinsufficiency disrupts the excitatory/inhibitory balance in the developing hippocampus and cortex and results in accelerated glutamatergic synapse maturation. When this process occurs during critical developmental windows, it alters the synaptic plasticity necessary for the refinement of connections that ultimately shape cognitive and behavioural modalities 4 9. Different SYNGAP1 protein isoforms exist and are generated through alternative splicing and alternative promoter usage, in a process regulated by synaptic activity and postnatal age in mice.…”

Molecular Dissection of Neuroligin 2 and Slitrk3 Reveals an Essential Framework for GABAergic Synapse Development

“…Mice were anesthetized and then perfused with 0.1 M phosphate buffer followed by 4% PFA plus 2% glutaraldehyde in the same buffer (Aceti et al, 2015) and brains were kept in fixative overnight. Then, brains were washed in phosphate-buffered saline and sliced at 125 μm.…”

Dendritic spine actin cytoskeleton in autism spectrum disorder

“…In mice, SynGAP1 accelerates the maturation of dendritic spines leading to disruptions in synaptic transmission and cognitive function [307][308][309][310] . Several de novo mutations of SYNGAP1 have also been associated with ASD 43,64,306,[311][312][313][314][315] .…”