# Autism Spectrum Disorders and Purinergic Signaling: A Systematic Review of Emerging Insights from Preclinical Studies **Authors:** Sonia Guha, David H. Elisha, Rebecca S. Eshraghi, Rahul Mittal, Richard C. Deth, Adrien A. Eshraghi PMC · DOI: 10.1007/s12031-026-02479-z · 2026-02-16 ## TL;DR This paper reviews preclinical studies showing how purinergic signaling dysfunction may contribute to autism spectrum disorders and could be a new therapeutic target. ## Contribution The paper systematically reviews emerging preclinical evidence linking purinergic signaling to the pathophysiology of ASD. ## Key findings - Aberrant purinergic receptor expression contributes to behavioral and synaptic abnormalities in ASD models. - Dysregulated ATP/adenosine levels and ectonucleotidase activity are linked to neuroinflammation and glial communication issues. - Purinergic signaling dysfunction is suggested as a potential therapeutic target for ASD. ## Abstract Autism Spectrum Disorders (ASD), are a group of complex neurodevelopmental conditions characterized by deficits in social communication and the presence of restricted, repetitive behaviors. ASD rates are rising alarmingly in the United States and the reason behind this is obscure. Increasing evidence suggests that purinergic signaling, a form of extracellular signaling mediated by purine nucleosides and nucleotides such as adenosine and adenosine triphosphate (ATP), plays a critical role in neurodevelopment and immune function. This systematic review summarizes preclinical studies focusing on the relationship between purinergic signaling pathways and ASD, focusing on molecular, cellular, and behavioral studies. A comprehensive literature search through 2024 was carried out in PubMed, Scopus, and Web of Science databases following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A total of 23 preclinical studies met our inclusion criteria and were included in the final review. The findings suggest that aberrant purinergic receptor expression, dysregulated ATP/adenosine status and ectonucleotidase level largely contribute to behavioral and synaptic abnormalities, dysregulation in neurotransmission, neuroinflammation and perturbed glial communication in ASD animal models. These insights support the hypothesis that purinergic signaling dysfunction contributes to the etiology and pathophysiology of ASD and represents a promising therapeutic target. ## Linked entities - **Chemicals:** adenosine (PubChem CID 60961), adenosine triphosphate (PubChem CID 5957), ATP (PubChem CID 5957) - **Diseases:** ASD (MONDO:0006664) ## Full-text entities - **Genes:** Ccl2 (C-C motif chemokine ligand 2) [NCBI Gene 20296] {aka HC11, JE, MCAF, MCP-1, MCP1, SMC-CF}, Il17a (interleukin 17A) [NCBI Gene 16171] {aka Ctla-8, Ctla8, IL-17, IL-17A, Il17}, Il1a (interleukin 1 alpha) [NCBI Gene 16175] {aka Il-1a}, Il1b (interleukin 1 beta) [NCBI Gene 16176] {aka IL-1beta, Il-1b}, Ccl5 (C-C motif chemokine ligand 5) [NCBI Gene 20304] {aka MuRantes, RANTES, SISd, Scya5, TCP228}, Tnc (tenascin C) [NCBI Gene 21923] {aka C130033P17Rik, Hxb, TN, TN-C, Ten, cytotactin}, Eif4e (eukaryotic translation initiation factor 4E) [NCBI Gene 117045], Nt5e (5' nucleotidase, ecto) [NCBI Gene 23959] {aka 2210401F01Rik, 5'-NT, CD73, NT, Nt5, eNT}, Mtor (mechanistic target of rapamycin kinase) [NCBI Gene 56717] {aka 2610315D21Rik, FRAP, FRAP2, Frap1, RAFT1, RAPT1}, Tsp1 (tumor suppressor region 1) [NCBI Gene 108314] {aka MTS}, Nlgn4l (neuroligin 4-like) [NCBI Gene 100113365] {aka NL-4, NL4, Nlgn4, Nlgn4x}, entpd8 (ectonucleoside triphosphate diphosphohydrolase 8) [NCBI Gene 436652] {aka si:ch211-10e8.4, zC10E8.4, zgc:92065}, P2rx1 (purinergic receptor P2X, ligand-gated ion channel, 1) [NCBI Gene 18436] {aka P2x, Pdcd3, RP-2}, Tlr4 (toll-like receptor 4) [NCBI Gene 21898] {aka Lps, Ly87, Ran/M1, Rasl2-8}, ADORA2A (adenosine A2a receptor) [NCBI Gene 135] {aka A2aR, ADORA2, RDC8}, ada2a (adenosine deaminase 2a) [NCBI Gene 373884] {aka cecr1, cecr1a, fj65e02, wu:fj65e02}, Camk2g (calcium/calmodulin-dependent protein kinase II gamma) [NCBI Gene 12325] {aka Camkg}, Adora2a (adenosine A2a receptor) [NCBI Gene 11540] {aka A2AAR, A2aR, AA2AR, ARA2A}, Ptpn5 (protein tyrosine phosphatase, non-receptor type 5) [NCBI Gene 19259] {aka Step}, Mtor (mechanistic target of rapamycin kinase) [NCBI Gene 56718] {aka Frap1, RAFT1}, Fos (Fos proto-oncogene, AP-1 transcription factor subunit) [NCBI Gene 14281] {aka D12Rfj1, c-fos, cFos}, Ifng (interferon gamma) [NCBI Gene 15978] {aka IFN-g, If2f, Ifg}, P2ry2 (purinergic receptor P2Y, G-protein coupled 2) [NCBI Gene 18442] {aka P2U1, P2Y2}, Ntrk2 (neurotrophic tyrosine kinase, receptor, type 2) [NCBI Gene 18212] {aka GP145-TrkB/GP95-TrkB, Tkrb, trk-B, trkB}, Thbs1 (thrombospondin 1) [NCBI Gene 21825] {aka TSP-1, TSP1, Thbs-1, tbsp1}, Il6 (interleukin 6) [NCBI Gene 16193] {aka Il-6}, Cd4 (CD4 antigen) [NCBI Gene 12504] {aka L3T4, Ly-4}, Eif4ebp1 (eukaryotic translation initiation factor 4E binding protein 1) [NCBI Gene 116636] {aka PHAS-I}, Aldh1l1 (aldehyde dehydrogenase 1 family, member L1) [NCBI Gene 107747] {aka 1810048F20Rik, FDH, Fthfd, Neut2}, Il1 (interleukin 1 complex) [NCBI Gene 111343] {aka Il-1}, Bdnf (brain derived neurotrophic factor) [NCBI Gene 12064], Il6 (interleukin 6) [NCBI Gene 24498] {aka ILg6, Ifnb2}, Gria1 (glutamate receptor, ionotropic, AMPA1 (alpha 1)) [NCBI Gene 14799] {aka 2900051M01Rik, Glr-1, Glr1, GluA1, GluR-A, GluRA}, Itpr2 (inositol 1,4,5-trisphosphate receptor, type 2) [NCBI Gene 81678], Tnf (tumor necrosis factor) [NCBI Gene 21926] {aka DIF, TNF-a, TNF-alpha, TNFSF2, TNFalpha, Tnfa}, Grin2b (glutamate receptor, ionotropic, NMDA2B (epsilon 2)) [NCBI Gene 14812] {aka GluN2B, GluRepsilon2, NR2B, Nmdar2b}, Fmr1 (fragile X messenger ribonucleoprotein 1) [NCBI Gene 14265] {aka FMRP, Fmr-1}, ada (adenosine deaminase) [NCBI Gene 436919] {aka zgc:92028}, Tgfb1 (transforming growth factor, beta 1) [NCBI Gene 21803] {aka TGF-beta1, TGFbeta1, Tgfb, Tgfb-1}, Nlrp3 (NLR family, pyrin domain containing 3) [NCBI Gene 216799] {aka AGTAVPRL, AII/AVP, Cias1, FCAS, FCU, MWS}, Itpr2 (inositol 1,4,5-triphosphate receptor 2) [NCBI Gene 16439] {aka InsP3R-2, InsP3R-5, Ip3r2, Itpr5, insP3R2}, Il10 (interleukin 10) [NCBI Gene 16153] {aka CSIF, If2a, Il-10}, Tbr1 (T-box brain transcription factor 1) [NCBI Gene 21375], P2ry1 (purinergic receptor P2Y1) [NCBI Gene 25265] {aka P2y, P2y1}, Stat3 (signal transducer and activator of transcription 3) [NCBI Gene 20848] {aka 1110034C02Rik, Aprf}, P2rx7 (purinergic receptor P2X, ligand-gated ion channel, 7) [NCBI Gene 18439] {aka P2X(7), P2X7R}, Gpbar1 (G protein-coupled bile acid receptor 1) [NCBI Gene 227289] {aka BG37, GPCR, GPR131, M-BAR, TGR5}, Gabrg2 (gamma-aminobutyric acid type A receptor, subunit gamma 2) [NCBI Gene 14406] {aka GABAA-R, Gabrg-2, gamma2}, ITPR2 (inositol 1,4,5-trisphosphate receptor type 2) [NCBI Gene 3709] {aka ANHD, CFAP48, INSP3R2, IP3R2}, Il9 (interleukin 9) [NCBI Gene 16198] {aka Il-9, P40}, Entpd1 (ectonucleoside triphosphate diphosphohydrolase 1) [NCBI Gene 12495] {aka 2610206B08Rik, ATP-DPH, Cd39, E130009M23Rik, NTPDase-1}, Gria2 (glutamate receptor, ionotropic, AMPA2 (alpha 2)) [NCBI Gene 14800] {aka GluA2, GluR-B, Glur-2, Glur2, gluR-K2}, Foxp3 (forkhead box P3) [NCBI Gene 20371] {aka JM2, scurfin, sf}, Syp (synaptophysin) [NCBI Gene 24804] {aka Syp1}, Rorc (RAR-related orphan receptor gamma) [NCBI Gene 19885] {aka Nr1f3, RORgamma, TOR, Thor}, P2ry12 (purinergic receptor P2Y, G-protein coupled 12) [NCBI Gene 70839] {aka 2900079B22Rik, 4921504D23Rik, P2Y12}, Grin2a (glutamate receptor, ionotropic, NMDA2A (epsilon 1)) [NCBI Gene 14811] {aka GluN2A, GluRepsilon1, NMDAR2A, NR2A}, Il2 (interleukin 2) [NCBI Gene 16183] {aka Il-2}, P2ry2 (purinergic receptor P2Y2) [NCBI Gene 29597] {aka P2Y2} - **Diseases:** ASD (MESH:D000067877), pain (MESH:D010146), conditions (MESH:D020763), inflammation (MESH:D007249), repetitive (MESH:D012090), metabolic disturbances (MESH:D024821), Autism (MESH:D001321), behavioral deficits (MESH:D019958), neurodevelopmental abnormalities (MESH:D063647), Neuroinflammation (MESH:D000090862), anxiety (MESH:D001007), Behavioral abnormalities (MESH:D001523), diabetic (MESH:D003920), Learning and memory deficits (MESH:D007859), neurodevelopmental anomalies (MESH:C567101), mood disorders (MESH:D019964), synaptic abnormalities (MESH:D012183), Social deficits (MESH:D009461), metabolic (MESH:D008659), FXS (MESH:D005600), hyperactivity (MESH:D006948), intellectual disabilities (MESH:D008607), brain deformities (MESH:D001927), sensorimotor coordination abnormalities (MESH:D001259), A2AR deficiency (MESH:D007153), malnutrition (MESH:D044342), viral infection (MESH:D014777), hypothermia (MESH:D007035), motility disorder (MESH:D015835), epilepsy (MESH:D004827), rubella (MESH:D012409), VAD (MESH:D014802), health (OMIM:603663), deficiency of the protein (MESH:D011488), social interactions (MESH:C563663), infection (MESH:D007239), GI dysfunction (MESH:D005767), immunologic dysfunction (MESH:D007154), neurodevelopmental pathologies (MESH:D005598), neuroimmune dysfunction (MESH:D006331), constipation (MESH:D003248), bacterial infection (MESH:D001424), depression (MESH:D003866), cognitive (MESH:D003072), neuropathy (MESH:D009422), behavioral and neurodevelopmental abnormalities (MESH:D002653), Communication deficits (MESH:D003147), immune dysregulation (OMIM:614878), MIA (MESH:D000079262), neurodevelopmental disorders (MESH:D002658) - **Chemicals:** oxygen (MESH:D010100), Inosine (MESH:D007288), adenosine (MESH:D000241), GMP (MESH:D006157), ADPbetaS (MESH:C030812), ADP (MESH:D000244), corticosterone (MESH:D003345), carbon (MESH:D002244), guanine (MESH:D006147), clonazepam (MESH:D002998), 17beta-estradiol (MESH:D004958), UA (MESH:D014527), PPADS (MESH:C077792), Poly(I:C) (MESH:D011070), IMP (MESH:D007291), ATPgammaS (MESH:C022571), AR-C 118925XX (MESH:C000706669), nucleotide (MESH:D009711), CGS 21680 (MESH:C061282), Vit A (MESH:D014801), alpha,beta-methylene-ATP (MESH:C002630), captisol (MESH:C093196), ARL67156 (MESH:C092431), tyrosine (MESH:D014443), purines (MESH:D011687), MCC950 (MESH:C000597426), UDP (MESH:D014530), L-kynurenine (MESH:D007737), glutamate (MESH:D018698), SCH 58261 (MESH:C098657), K+ (MESH:D011188), Na+ (MESH:D012964), Ca2+ (-), VA (MESH:D014635), phenylalanine (MESH:D010649), Istradefylline (MESH:C111599), JNJ 47965567 (MESH:C000590736), LPS (MESH:D008070), TAK242 (MESH:C507035), lipid (MESH:D008055), purine (MESH:C030985), nucleoside (MESH:D009705), 6-hydroxymelatonin (MESH:C012365), AMP (MESH:D000249), BzATP (MESH:C033901), ATP (MESH:D000255), glutathione (MESH:D005978), glucose (MESH:D005947), MRS2500 (MESH:C495475), 2-aminobenzoic acid (MESH:C031385), calcium (MESH:D002118), UTP (MESH:D014544), NAD + (MESH:D009243), Suramin (MESH:D013498), tryptophan (MESH:D014364) - **Species:** Adeno-associated virus (species) [taxon 272636], Mus musculus (house mouse, species) [taxon 10090], Danio rerio (leopard danio, species) [taxon 7955], Homo sapiens (human, species) [taxon 9606], Rattus norvegicus (brown rat, species) [taxon 10116] - **Mutations:** A2A - **Cell lines:** BTBR — Mus musculus (Mouse), Embryonic stem cell (CVCL_2H76), /6 — Homo sapiens (Human), Tongue squamous cell carcinoma, Cancer cell line (CVCL_5985), B6 — Homo sapiens (Human), Finite cell line (CVCL_L814), C57BL/6 — Mus musculus (Mouse), Transformed cell line (CVCL_C0MU), C58 — Oncorhynchus mykiss (Rainbow trout), Spontaneously immortalized cell line (CVCL_S157) ## Figures 6 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12909453/full.md --- Source: https://tomesphere.com/paper/PMC12909453