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Table 2 Summary of synaptic phenotypes identified in hPSC models of ASD

From: Modeling neuronal consequences of autism-associated gene regulatory variants with human induced pluripotent stem cells

Gene/locus Case/ctrl1 or isogenic Cell types Culture system2 Synaptic phenotype3 Phenotype rescued? Ref
Excit Inhib4
22q13.3+/− Case/ctrl Neurons (NPC) ASD/Ctrl co-culture w/ rt astro ↓ sEPSC freq/ampl;
↓ exc syn#;
↓ AMPAR ampl;
↓ NMDAR ampl
No change IGF-1 or SHANK3 transgene [34]
TRPC6+/− Case/ctrl Neurons (NPC) Mono-culture ↓ vGLUT1 punctae;
↓ TDL
ND IGF-1, TRPC6 transgene, and TRPC6 agonist [35]
NRXN1+/− Isogenic hESC Excit neu (Ngn2) Mono-culture w/ ms astro ↓ mEPSC freq;
↓ release prob;
=syn#; =TDL
NA Not tested [36]
STXBP1+/− Isogenic hESC Excit neu (Ngn2) Mono-culture w/ ms astro ↓ mEPSC freq;
↓ release prob;
= syn#; =TDL
NA Not tested [37]
SHANK3−/− Isogenic hESC Excit neu (Ngn2) Mono-culture ↓ mEPSC freq;
↓ syn#;
↓ Ih channel function
NA Not tested [38]
ASD with macrocephaly Case/ctrl Neurons (NPC) Mono-culture ↓ vGLUT1 punctae;
↓ burst freq
ND IGF-1 (network bursts) [39]
Not stratified Case/ctrl Neurons and astro (NPC) Reciprocal neu/astro for ASD and Ctrl ↓ exc syn#;
↓ firing rate;
(caused by ASD astro)
ND Culture ASD neurons w/ctrl astro or block IL-6 [40]
10 ASD genes knocked-out with CRISPR Isogenic iPSCs Excit neu (Ngn2) Mono-culture w/ms astro ↓ sEPSC freq (5/10 genes);
↓ burst freq (4/10 genes)
NA Not tested [32]
CNTN5+/− and EHMT2+/− Case/ctrl and isogenic Excit neu (Ngn2) Mono-culture w/ms astro ↑ firing rate;
↑ burst freq
NA Not tested [42]
NLGN4R704C Isogenic hESC Neurons (Excit: AM; Inhibit: AD) Mono-culture or co-culture on ctrl lawn w/ ms astro ↑ syn#;
↑ mEPSC freq/ampl
No change Not tested [43]
SHANK2+/− Case/ctrl and isogenic Neurons (NPC) ASD/Ctrl co-culture on ctrl lawn w/ms astro ↑ syn#;
↑ TDL;
↑ sEPSC freq/ampl
ND Genome editing to repair SHANK2 and DHPG [41]
PTCHD1-AS-/y Case/ctrl and isogenic Neurons (NPC) Mono-culture w/hu or ms astro ↓ AMPAR-mEPSC freq;
=exc syn#; =TDL;
↓ NMDAR ampl
ND Not tested [20]
9q34+/− or EHMT1+/− Case/ctrl and isogenic Excit neu (Ngn2) Mono-culture w/rt astro ↓ burst freq;
↑ burst duration
=syn#; =TLD; =AMPAR-mEPSC freq/ampl;
↑ NMDAR ampl
NA MK-801 [44]
  1. 1Case/ctrl iPSC-derived neurons from people with ASD compared to neurons from unaffected controls (ctrl)
  2. 2Astro astrocytes, rt rat, ms mouse, hu human
  3. 3Excit excitatory, Inhib inhibitory, sEPSC spontaneous excitatory postsynaptic current, Freq frequency, Ampl amplitude, exc syn# excitatory synapse number or density, AMPAR ampl amplitude of AMPA receptor-dependent currents, NMDAR ampl amplitude of NMDA receptor-dependent currents, vGLUT1 vesicular glutamate transporter (pre-synaptic marker of excitatory synapses), TDL total dendrite length or neurite length, mEPSC miniature excitatory postsynaptic current, release prob probability of presynaptic neurotransmitter release, syn# synapse number or density, burst freq network bust frequency (measured by MEA), firing rate mean firing rate (measured by MEA), AMPAR-mEPSC AMPAR receptor-dependent mEPSC, burst duration network bust duration (measured by MEA)
  4. 4ND not determined, NA not applicable (Ngn2 neurons are excitatory)