This hypothesis proposes that lncRNA-9969's selective sequestration of miR-6361 in parvalbumin interneurons operates through a sophisticated two-factor molecular recognition system inherited from general lncRNA-miRNA binding principles. Upon CREB1 activation in PV interneurons, transcriptionally upregulated lncRNA-9969 employs both canonical seed-complementary sites and favorable local secondary structures to achieve high-affinity, specific binding to miR-6361. This dual recognition mechanism explains why lncRNA-9969 can selectively compete for miR-6361 despite the presence of other seed-sharing microRNAs in the cellular environment. The seed complementarity provides initial target recognition, while specific RNA structural motifs around the binding sites create the thermodynamic favorability needed for effective competitive sequestration. This selectivity is crucial because PV interneurons express multiple microRNAs with overlapping seed sequences, yet lncRNA-9969 must specifically titrate miR-6361 to derepress autophagy genes (ATG5, ATG7, BECN1, LC3B) without disrupting other miRNA regulatory networks.

This hypothesis proposes that lncRNA-9969's selective sequestration of miR-6361 in parvalbumin interneurons operates through a sophisticated two-factor molecular recognition system inherited from general lncRNA-miRNA binding principles. Upon CREB1 activation in PV interneurons, transcriptionally upregulated lncRNA-9969 employs both canonical seed-complementary sites and favorable local secondary structures to achieve high-affinity, specific binding to miR-6361. This dual recognition mechanism explains why lncRNA-9969 can selectively compete for miR-6361 despite the presence of other seed-sharing microRNAs in the cellular environment. The seed complementarity provides initial target recognition, while specific RNA structural motifs around the binding sites create the thermodynamic favorability needed for effective competitive sequestration. This selectivity is crucial because PV interneurons express multiple microRNAs with overlapping seed sequences, yet lncRNA-9969 must specifically titrate miR-6361 to derepress autophagy genes (ATG5, ATG7, BECN1, LC3B) without disrupting other miRNA regulatory networks. The structural component likely involves base-pairing beyond the seed region and local hairpin formations that stabilize the lncRNA-miRNA duplex. This mechanism predicts that mutations disrupting either the seed complementarity or the secondary structure elements would proportionally reduce binding affinity and ceRNA function. The cell-type specificity emerges from CREB1-driven transcriptional control ensuring lncRNA-9969 expression primarily in activated PV interneurons, creating a spatially restricted ceRNA network that links gamma oscillation activity to autophagy regulation through precise molecular recognition.