Excitation/Inhibition Imbalance in Autism Rodent Models

E/I IMBALANCE AND AUTISTIC-LIKE BEHAVIORS:

• Optogenetic stimulation of pyramidal neurons in the medial prefrontal cortex in mice induces social deficits associated with enhanced gamma oscillations.
• Increased neocortical E/I ratio caused by malfunctions of PV-expressing interneurons induces excessive gamma oscillations and autistic-like behaviors.

Factors Contributing to E/I Imbalance

• E/I balance at the circuit level involves the interplay between GABAergic interneurons and target pyramidal neurons, modulating long-range connections.

Excitatory Synapse Development

• Neuroligin and neurexin genes play critical roles in synapse and circuit development.
• Knockout of 4E-BP2 in mice upregulates neuroligins, increases hippocampal synaptic E/I ratio, and induces autistic-like behaviors.
• Pharmacologic inhibition of eIF4E or knockdown of neuroligin-1 normalizes the E/I ratio and rescues autistic-like behaviors.

AMPAR 

• Ampakine rescues impaired long-term potentiation and long-term memory in Ube3a-deficient mice, a model of Angelman syndrome.
• Various gene mutations affect AMPAR transmission and synaptic functions in different mouse models.
• IGF-1 treatment rescues reduced excitatory transmission in Shank3 and Mecp2 mice.

NMDAR

• Mutations in genes like Nlgn1, Shank2, and Tbr1 lead to NMDAR hypofunction and social deficits in mice.
• Both hypo- and hyperfunction of NMDARs can cause autistic-like behaviors in animal models.
• mGluR5 hyperfunction in Fmr1 and BTBR mice is implicated in ASDs.

Signaling Pathways

• The mTOR pathway and actin-modulatory pathways play crucial roles in rescuing autistic-like phenotypes in animal models.
• Dopamine receptor agonists/antagonists and 5-hydroxytryptamine rescue behaviors in various mouse models.

Inhibitory Synapse Development and Function

• Deletion of inhibitory synapse-specific Nlgn2 leads to decreased inhibitory synapse density and cognitive deficits.
• Mutations in genes like Nlgn3 and Cntnap2 affect GABAergic transmission in different brain regions.
• Deficiencies in GABA A receptor subunits and altered tonic GABAergic transmission are observed in ASD model animals.

Interneurons

• PV interneurons are crucial for regulating gamma oscillations and are associated with psychiatric disorders.
• Defects in PV, SST, and NPY interneurons lead to various phenotypes in mouse models.
• Reduced interneuronal firing and GABAergic output contribute to social and cognitive deficits in ASD models.

Glial Cells

• Astrocytes and nonastrocytic glial cells like microglia and oligodendrocytes play roles in regulating excitatory synapse structure and function.
• Re-expression of MeCP2 in glial cells can restore disease-related phenotypes in ASD models.

Intrinsic Neuronal Excitability

• Deficits in dendritic ion channels and intrinsic excitability are observed in various mouse models.
• Neuregulin-ErbB4 signaling modulates the intrinsic excitability of PV interneurons.Homeostatic 

Synaptic Plasticity

• Fmr1 mice show altered synaptic scaling in different brain regions.
• GKAP/DLGAP1/SAPAP1 scaffold regulates bidirectional synaptic scaling in the hippocampus.

Temporal E/I Regulation

• Temporal changes in E/I balance are crucial for normal brain development.
• Early interventions with specific inhibitors can normalize E/I balance and rescue abnormal phenotypes in animal models.
• Delayed restoration of certain genes can also rescue abnormal phenotypes in ASD models.

Perspectives

• Careful interpretation of rescue results is necessary to understand the fundamental correction of pathogenic mechanisms.

Lee, E., Lee, J., & Kim, E. (2017). Excitation/inhibition imbalance in animal models of autism spectrum disorders. Biological psychiatry, 81(10), 838-847.