Postsynaptic Scaffold Disruption
trigger
The proximal molecular lesion: loss of function (typically haploinsufficiency) of a postsynaptic-density scaffold or scaffold-regulatory protein at glutamatergic synapses. These proteins organize the PSD and couple membrane glutamate receptors (NMDA, AMPA) to downstream signaling and the actin cytoskeleton. Conforming entries substitute the disease gene and its specific molecular role (structural scaffold for SHANK3; postsynaptic Ras-GAP that maintains PSD organization for SYNGAP1).
Downstream
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Excitatory Postsynaptic Structural Deficit
Loss of the PSD organizer degrades excitatory postsynaptic structure and receptor organization.
Show evidence (2 references)
"Almost all of these deletions include the gene SHANK3 which encodes a scaffold protein in the postsynaptic densities of excitatory synapses, connecting membrane-bound receptors to the actin cytoskeleton."
Establishes the postsynaptic-scaffold framing for SHANK3, the prototype gene for this module's trigger node.
"SYNGAP1-related disorder (SRD) is a monogenic synaptopathy caused"
SYNGAP1-related disorder is framed as a monogenic synaptopathy, a second conforming example of postsynaptic-scaffold disruption.
Excitatory Postsynaptic Structural Deficit
central effector
Disruption of the scaffold reduces structural organization and maturation of the excitatory postsynaptic compartment: fewer structurally mature glutamatergic synapses, destabilized PSD architecture, and impaired localization or trafficking of AMPA/NMDA-type glutamate receptors.
Used by disorders
Epilepsy
as Postsynaptic Density Destabilization
Downstream
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Impaired Synaptic Plasticity and Excitatory-Inhibitory Imbalance
Reduced excitatory synaptic structure lowers excitatory output and disrupts the E/I set point.
Impaired Synaptic Plasticity and Excitatory-Inhibitory Imbalance
central effector
Reduced excitatory glutamatergic transmission and impaired activity-dependent plasticity shift the balance between excitation and inhibition. In some genotypes the structural deficit selectively reduces excitatory (not inhibitory) transmission; in others, dysregulated signaling locks synaptic plasticity into an abnormal state. The shared consequence is an altered E/I balance at the synaptic level.
Downstream
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Circuit-Level Dysfunction
Synaptic-level E/I imbalance and plasticity deficits propagate to aberrant circuit assembly and dynamics.
Show evidence (1 reference)
"We show that PMDS neurons have reduced SHANK3 expression and major defects in excitatory, but not inhibitory, synaptic transmission."
Human iPSC-derived neurons show selective excitatory (not inhibitory) synaptic deficits, the cellular signature of E/I imbalance in this module.
Circuit-Level Dysfunction
consequence
Synaptic deficits aggregate into circuit-level pathology: aberrant cortical or cortico-striatal circuit assembly, abnormal connectivity and oscillatory dynamics, and network-level hyper- or hypo-excitability. The specific circuit and anatomical locus are disease-dependent (e.g. cortico-striatal circuits in SHANK3 models; cortical circuit consolidation in SYNGAP1).
Used by disorders
Epilepsy
as Cortical Circuit Hard-Wiring
Downstream
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Neurodevelopmental Phenotypic Output
Circuit dysfunction manifests as the neurodevelopmental and neuropsychiatric phenotype.
Show evidence (1 reference)
"Cellular, electrophysiological and biochemical analyses uncovered defects at striatal synapses and cortico-striatal circuits in Shank3 mutant mice."
Shank3 mutant mice show cortico-striatal circuit defects, illustrating progression from synaptic scaffold loss to circuit-level dysfunction.
Neurodevelopmental Phenotypic Output
consequence
The clinical convergence point: excitatory-synapse scaffold disruption produces a neurodevelopmental phenotype spanning autism spectrum disorder, intellectual disability, developmental delay, and/or epilepsy. The relative weighting of features is genotype- and circuit-dependent.