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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/locusCase/ctrl1 or isogenicCell typesCulture system2Synaptic phenotype3Phenotype rescued?Ref
22q13.3+/−Case/ctrlNeurons (NPC)ASD/Ctrl co-culture w/ rt astro↓ sEPSC freq/ampl;
↓ exc syn#;
↓ AMPAR ampl;
↓ NMDAR ampl
No changeIGF-1 or SHANK3 transgene[34]
TRPC6+/−Case/ctrlNeurons (NPC)Mono-culture↓ vGLUT1 punctae;
NDIGF-1, TRPC6 transgene, and TRPC6 agonist[35]
NRXN1+/−Isogenic hESCExcit neu (Ngn2)Mono-culture w/ ms astro↓ mEPSC freq;
↓ release prob;
=syn#; =TDL
NANot tested[36]
STXBP1+/−Isogenic hESCExcit neu (Ngn2)Mono-culture w/ ms astro↓ mEPSC freq;
↓ release prob;
= syn#; =TDL
NANot tested[37]
SHANK3−/−Isogenic hESCExcit neu (Ngn2)Mono-culture↓ mEPSC freq;
↓ syn#;
↓ Ih channel function
NANot tested[38]
ASD with macrocephalyCase/ctrlNeurons (NPC)Mono-culture↓ vGLUT1 punctae;
↓ burst freq
NDIGF-1 (network bursts)[39]
Not stratifiedCase/ctrlNeurons and astro (NPC)Reciprocal neu/astro for ASD and Ctrl↓ exc syn#;
↓ firing rate;
(caused by ASD astro)
NDCulture ASD neurons w/ctrl astro or block IL-6[40]
10 ASD genes knocked-out with CRISPRIsogenic iPSCsExcit neu (Ngn2)Mono-culture w/ms astro↓ sEPSC freq (5/10 genes);
↓ burst freq (4/10 genes)
NANot tested[32]
CNTN5+/− and EHMT2+/−Case/ctrl and isogenicExcit neu (Ngn2)Mono-culture w/ms astro↑ firing rate;
↑ burst freq
NANot tested[42]
NLGN4R704CIsogenic hESCNeurons (Excit: AM; Inhibit: AD)Mono-culture or co-culture on ctrl lawn w/ ms astro↑ syn#;
↑ mEPSC freq/ampl
No changeNot tested[43]
SHANK2+/−Case/ctrl and isogenicNeurons (NPC)ASD/Ctrl co-culture on ctrl lawn w/ms astro↑ syn#;
↑ TDL;
↑ sEPSC freq/ampl
NDGenome editing to repair SHANK2 and DHPG[41]
PTCHD1-AS-/yCase/ctrl and isogenicNeurons (NPC)Mono-culture w/hu or ms astro↓ AMPAR-mEPSC freq;
=exc syn#; =TDL;
↓ NMDAR ampl
NDNot tested[20]
9q34+/− or EHMT1+/−Case/ctrl and isogenicExcit neu (Ngn2)Mono-culture w/rt astro↓ burst freq;
↑ burst duration
=syn#; =TLD; =AMPAR-mEPSC freq/ampl;
↑ NMDAR ampl
  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)