Table 1.

Differentially Expressed Genes in iMSN^D2HET

Gene Symbol	FC	padj	Gene Name and Notes	References
Upregulated
Fxyd2	2.20	4 × 10−13	FXYD domain-containing ion transport regulator 2; modulatory γ-subunit of the Na/K pump; associated with schizophrenia and nicotine addiction	(47)
Pde1c	1.49	2 × 10−6	Phosphodiesterase 1C; degrades cAMP/cGMP; intronic variant associated with smoking phenotypes by GWAS	(48,49)
Igfbp6	1.67	3 × 10−4	Insulin-like growth factor binding protein 6; activates the MAPK signaling pathway; role in neurogenesis in the hippocampus	(50)
Spon1	1.50	.001	Spondin 1; secreted extracellular protein; role in neurite growth and axon guidance; genetic variant on its locus associated with cognitive decline by GWAS	(51,52)
Nrn1l	2.12	.002	Neuritin 1-like; extracellular protein; enhances neurite growth and neuronal survival
Gad1	1.23	.010	Glutamate decarboxylase 1; key enzyme of GABA synthesis
Lypd1	1.34	.010	Ly6/Plaur domain containing 1 (aka Lynx2); modulator of nicotinic acetylcholine receptors; KO mouse model displays increased anxiety-related behavior	(53,54)
Crem	1.40	.020	cAMP-responsive element modulator; multiple alternative-splice isoforms acting as activators and repressors of transcription; paralog to Creb1; increased expression reduced impulsive action in an attention deficit hyperactivity disorder (ADHD) animal model	(55,56)
Nptx2	1.46	.039	Neuronal pentraxin 2; involved in synapse formation, specifically AMPA receptor clustering	(57)
Cartpt	2.19	.067	CART prepropeptide; modulates cocaine and dopamine effects in the striatum	(58,59)
Downregulated
Stc1	−1.90	2 × 10−11	Stanniocalcin 1; glycoprotein involved in calcium/phosphate homeostasis
Gpx6	−2.11	2 × 10−7	Glutathione peroxidase 6; neuroprotective against oxidative and other forms of stress; in a Huntington disease mouse model, upregulation in striatum improved behavioral and molecular phenotypes	(60,61)
Fam163b	−1.62	3 × 10−6	Family with sequence similarity 163, member B; membrane protein of unknown function; implicated in tobacco use disorder and stress	(62,63)
Cnih3	−1.62	6 × 10−6	Cornichon family AMPA receptor auxiliary protein 3
Gstm6	−1.86	9 × 10−6	Glutathione S-transferase mu 6; neuroprotective against oxidative and other forms of stress	(60)
Slc24a3	−1.59	7 × 10−5	Solute carrier family 24, member 3; plasma-membrane potassium-dependent sodium-calcium exchanger, a druggable target for treatment; intronic variant associated with externalizing behavior by GWAS	(64,65)
Id4	−1.36	7 × 10−5	Inhibitor of DNA binding 4; inhibitory transcription factor; required for the correct timing of neural differentiation	(66)
Cdh13	−1.38	3 × 10−4	Cadherin 13 (aka T-cadherin); GPI-anchored cell adhesion molecule; inhibits neural growth and signals through ERK pathway; impacts GABAergic function; accumulative evidence of association with SUDs from GWAS	(65,67, 68, 69)
S100a10	−1.68	.036	S100 calcium binding protein A10 (calpactin); membrane protein involved in neurotransmitter transport; associated with depression and cocaine reward	(70)
Mapk3	−1.20	.071	Mitogen-activated protein kinase 3; MAPK/ERK pathway involved in growth	(32,57)

List of 20 genes upregulated (top) and downregulated (bottom) in iMSN^D2HET (p_adj ≤ 0.1) with relevant function notes; p_adj is the p value adjusted for multiple testing (false discovery rate).

ADHD, attention-deficit/hyperactivity disorder; cAMP, cyclic adenosine monophosphate; CART, cocaine- and amphetamine-regulated transcript protein; cGMP, cyclic guanosine monophosphate; ERK, extracellular signal-regulated kinase; FC, fold change; GABA, gamma-aminobutyric acid; GPI, glycosylphosphatidylinositol; GWAS, genome-wide association study; iMSN, indirect medium spiny neuron; KO, knockout; MAPK, mitogen-activated protein kinase; SUDs, substance use disorders.