This challenge targets the hypothesis: **Prefrontal sensory gating circuit restoration via PV interneuron enhancement** **Hypothesis Summary:** ## Molecular Mechanism and Rationale Parvalbumin-expressing (PV+) interneurons represent the most abundant class of GABAergic interneurons in the prefrontal cortex (PFC), comprising approximately 40% of all cortical inhibitory neurons. These fast-spiking interneurons are characterized by their unique molecular signature, including high expression of the calcium-binding protein parvalbumin (PVALB), the voltage-gated potassium channel subunit Kv3.1b (KCNC1), and the GABA transporter GAT-1 (SLC6A1 **Falsifiable Predictions:** 1. Pharmacological modulation of PVALB will alter Alzheimer's disease markers in validated models by ≥20% 2. Genetic knockdown of the key target will reproduce the pathological phenotype in ≥2 independent model systems 3. Patient-derived biosamples will show the predicted molecular signature (sensitivity ≥70%, specificity ≥70%) 4. Mechanistic intervention at the proposed node will rescue neuronal viability in vitro by ≥30% **Bounty Tier:** $127,517 USD (composite score 0.775) **Challenge Type:** Open — any team may submit experimental evidence supporting or refuting this hypothesis **Success Criteria:** Peer-reviewed evidence demonstrating mechanistic validation of ≥2 of the 4 predictions, with independent replication.