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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)