Table 1.

Ionotropic Glutamate Receptor Alterations in Animal Models of ASD and FXS

Animal Model/ Targeted Gene-protein	Brain Region/s Studied	iGluR Alterations	Functional Alterations	Behavioral Characteristics	Drug Treatment and Effects	References
Fmr1 KO/FMRP	PFC	↓synaptic insertion of GluA1, ↓GluN2B phosophorylation	↓D1R facilitation of LTP in PFC, ↑gpI mGluR activity	hyperactivity, learning deficits	combined SKF81297 and DL-AP3 rescue deficient GluN2B phosphorylation, reduce hyperactivity and improve learning	[186,187]
Fmr1 KO/FMRP	PFC	↓GluN1,↓GluN2A, ↓GluN2B, ↓PSD-95, ↓SAPAP3,↓Arc		cognitive impairment in acquisition of visual- spatial discrimination task		[188]
Fmr1 KO/FMRP	hippocampus	↔ in GluN1, ↔GluN2A, ↔GluN2B by Western blot; 3’UTR translation assay suggests ↑GluN2A at 1-2 weeks				[192]
Fmr1 KO2/FMRP	CA1 hippocampus	↓synaptic GluA1 and ↓GluA2 at 14 days, ↑synaptic GluN1 at 14 days and not at 6-7 weeks	↓AMPA/ NMDA ratio due to ↓AMPA and ↑NMDA currents at 14 days but not at 6-7 weeks, ↑NMDAR-LTP ↔NMDAR-LTD		MPEP does not have a blocking effect on enhanced NMDAR-LTP at 14 days	[174]
Fmr1 KO/FMRP	CA1 hippocampus	↓synaptic delivery of GluA1	↓LTP, ↓Ras-PI3K-PKB signaling		Ras overexpression restores GluA1 delivery and LTP; PI3K inhibitor blocks LTP	[194]
Fmr1 KO/FMRP	CA1 hippocampus	DHPG induces ↓GluA1 and ↓GluA2/3	↑mGluR-LTD			[234]
Fmr1 KO/FMRP	CA1 hippocampus	↓GluA2	↑mGluR-LTD	↑audiogenic seizures, abnormal social and non-social anxiety-related behaviors	Genetic decrease of STEP diminishes audiogenic seizures and restores social and anxiety-related behaviors	[237, 242]
Fmr1 KO/FMRP	CA1 hippocampus	Absent retinoic-acid (RA)-dependent translation of GluA1 in dendrites	RA-mediated synaptic scaling is abolished		Postsynaptic expression of FMRP with lentivirus in Fmr1 KO neurons restores synaptic scaling	[86]
Fmr1 KO/FMRP	Anterior piriform cortex	↓ synaptic NMDA receptors	↓LTP			[173]
Fmr1 KO/FMRP	Amygdala	↓GluA1	↓mGluR-LTP at thalamic afferents to lateral amygdala (LA)		MPEP fails to rescue LTP deficit in LA but restores deficits in presynaptic release	[182]
MeCP2 KO (Rett syndrome)	Nucleus tractus solitarius (nTS), mPFC, cingulate cortex		↑hyperexcitability in nTS, enhanced spontaneous, evoked excitatory mEPSCs in nTS; hypoactivity in mPFC and cingulate cortex	altered Fos expression – ↑ in nTS, ↓ in mPFC and cingulate cortex; abnormal PPI of acoustic startle	ketamine (NMDAR antagonist) rescues abnormal PPI of acoustic startle and normalizes Fos expression	[198]
MeCP2 KO (Rett syndrome)	Entire brain and hippocampus	↓synaptic GluA2/3, ↓GluN2A receptors and other synaptic proteins (↓Vglut1, ↓Synapsin1, ↓CamKIIα and CamKIIβ), ↓GABABR2		↓activity, ↓forelimb strength with shorter fall latency, ↓motor coordination, symptoms worse in female mice		[199]
Tsc1 KO (using viral delivery of Cre recombinase in select neurons)	hippocampus CA1		↑evoked AMPA and ↑evoked NMDA synaptic currents, abolished mGluR-LTD, ↔ NMDAR-LTD			[200]
Rats bred for low rates of play-induced pro-social USV				↓social contact time, ↓play-induced pro-social USV, ↑monotonous USV	NMDAR glycine partial agonist GLYX-13 rescues deficits in play-induced USV and ↓ monotonous USV	[22]
Balb/c mice (inbred) Swiss-Webster mice (outbred)				impaired measures of sociability in 4 and 8-week old mice	D-cycloserine (NMDAR glycine site agonist) improves sociability in both mouse strains; MPEP impairs measures of sociability in both strains	[203,204]
Constitutive GluN1 KO mice	cortex	85‰ ↓ GluN1	neuronal hypexcitability and ↑E/I balance; ↓gamma signal-to-noise ratio (SNR)	↓ social preference, impaired spatial memory	GABAB agonist baclofen improves E/I balance, gamma SNR, reverses behavioral deficits	[207]
Parvalbumin (PV) interneuron-selective GluN1KO mice	cortex	selective ↓GluN1 in PV interneurons		↓N1 latency ↓sociability ↓premating USV power		[208]
Islet Brain-2 protein lacking mice (IB2-/-)	cerebellum	no change in GluA2, GluN1, GluN2A and GluN2B, altered Purkinje cell morphology with thinner dendrites	↓AMPAR and ↑NMDAR-mediated transmission at cerebellar mossy fiber-granule cell synapses,↓ delayed AMPA/kainate neuro- transmission at cerebellar fiber to Purkinje cell synapses	↓ social interactions, impaired exploration of novel environment, motor performance and learning deficit on rotarod		[225]
Ube3A KO mice (Angelman syndrome)	hippocampus	↓synaptic GluA1 ↑ GluA1 endocytosis ↑Arc	Altered AMPAR function - ↓mEPSC frequency; ↓AMPA/NMDA ratio	High frequency of seizures, ataxia, abnormal EEGs, poor performance on learning and memory tests	Decreasing Arc using shRNA restores normal synaptic GluA1 levels	[245]
GluK2 KO mice	Hippocampus (mossy fiber-CA3 synapses)	↓GluA1	Delayed functional maturation of mf-CA3 synapses; ↓amplitude of AMPA EPSC			[251]

The table summarizes studies of animal models of ASD and FXS that are discussed in the text involving changes in iGluRs, and presents the associated molecular/neuroanatomical, functional and behavioral alterations. The numbers in the “References” column refer to the citation numbers in the text. ↔ - no change; ↓ - decrease; ↑- increase. For ease of comparison of the results between the studies, each study is presented separately in a row, even if the same animal model is used (e.g., the Fmr1 KO mouse). It is evident that in one animal model changes may affect more than one iGluR subtype such as AMPA and NMDA receptors. If a treatment approach (pharmacological drug or genetic approach) is used in the study to correct the iGluR levels, functional and/or behavioral changes, it is indicated in the table. In the Fmr1 KO mouse, administration of mGlu5 receptor antagonists such as MPEP, MTEP, fenobam and CTEP in animal models has shown therapeutic promise in reversing biochemical, neuroanatomical, synaptic plasticity and behavioral aberrations associated with FXS, but these studies are not indicated here because the focus of the review is on iGluRs.