Identifying fundamental mechanisms of cognition that may be harnessed to prevent or reverse pathological cognitive aging, the biggest risk factor for Alzheimer's disease, motivated our foray into aging when I started the lab. Great to see this thoughtful write up of our discovery of a secreted phospholipase encoding a cognitive resilience sentinel in aging in alzforum. It does a great job placing our discovery within the larger context of lipid neuro/glial biology in aging and AD which remains one active focus of the Sahay lab. alzforum.org/news/research-n…

Excited to share our discovery of a convergent mechanism for cognitive restoration and seizure suppression in neurodevelopment disorders published on this day of a total solar eclipse, August 12, 2026 (“Procognitive restoration of PV neuron plasticity in neurodevelopmental disorders”, Open Access in Nature nature.com/articles/s41586-0…). This work was spearheaded by two amazing neuroscientists, Yu-Tzu Shih PhD (Assistant Professor, TBA) and @Jason_Alipio, + other major contributors from the Sahay lab: @al0k_91 (in vivo physiology), Nathaniel Green (ensemble tagging) and terrific collaborators, @DullaChris and Zin-Juan Klaft PhD (Tufts, ECoG recordings), @omarahmedlab (University of Michigan, SWR analysis), @Hyun_neuron_10Jung(DGIST, reagents). Background and the Challenge Cognitive impairment and seizures are hallmarks of neurodevelopmental disorders or NDDs and represent a large clinical unmet need. Significant advances in the genetics of neurodevelopmental disorders have identified high confidence risk genes for autism spectrum disorder (many of which define rare diseases, sfari.org), bipolar disorder, schizophrenia and epilepsy. Additionally, these sequencing efforts have revealed shared genetic architectures underlying these NDDs. Two major challenges emerge from these findings. First, defining circuit-based instantiations of shared genetic architectures as they relate to cognition and regulation of network excitability. Second, identifying convergent circuit mechanisms that may be reinstated for cognitive restoration and seizure suppression in NDDs. The discovery Impaired experience-dependent refinement of inhibitory circuits during the early postnatal period is thought to contribute to NDDs. Parvalbumin inhibitory neurons (PV INs) dynamically change their intrinsic excitability, input-output connectivity, synaptic physiology and synaptic plasticity in response to experience (referred to here as “Experience-dependent parvalbumin inhibitory neuron plasticity”)to precisely control neuronal spiking, neuronal ensembles, network oscillations and network excitability. Our knowledge of regulators of experience-dependent parvalbumin inhibitory neuron plasticity in the hippocampus is scant. In a first of its kind input-specific translatome screen designed to identify regulators of experience-dependent parvalbumin inhibitory neuron plasticity or XPGs in the adult hippocampus (region CA3/CA2) of mice, we discovered a large suite of ultra-high confidence risk genes for ASD, bipolar disorder, schizophrenia and epilepsy as candidate XPGs. Many of these candidate XPGs encode for transcription factors and chromatin regulators whose functions in PV INs are not known. The expression of these XPGs is negligibly low but is upregulated by experience. Understanding how XPGs in the hippocampus control PV IN properties, feed-forward inhibition, and synaptic plasticity will generate insights into formation and storage of spatial and social memories, as well as hippocampal communication with different brain regions to calibrate many different behaviors including social behavior. We show in proof-of-concept studies that selectively expressing one candidate XPG, the transcription factor Meis2, in PV INs of hippocampal subregion CA3/CA2 in a widely used NDD risk mouse model is sufficient to re-instate experience-dependent parvalbumin inhibitory neuron plasticity and reverse developmental deficits in feed-forward inhibition, synaptic plasticity (iLTD), neuronal ensembles, sharp wave-ripples, spatial and social cognition. Boosting Meis2 expression in PV INs also suppressed seizures. MEIS2 regulates a module of genes encoding for chromatin regulators, synaptic proteins, synaptic adhesion molecules, cytoskeletal proteins, ion channels, and axon guidance factors that together define a distinct PV inhibitory neuron cell state. Is your favorite gene a candidate XPG? Check out our XPG NDD portal: XPG site: xpg-atlas.onrender.com/) Impact and next steps This study builds on our prior work and suggests that PV INs transition through distinct cell states in response to experience to expand the capacity for cognitive operations. Ongoing efforts are aimed at linking cell states with emergent network states. Deciphering the XPG code within PV INs will inform how PV INs toggle between different modes of inhibition (blanket vs. sculpted) of principal cells to dictate neuronal spiking, ensembles and sharp wave-ripples. Since the principal cell-PV IN-principal cell feed-forward inhibition motif is found in circuits supporting memory, sensory processing, cognitive flexibility, decision making and attention, targeting experience-dependent PV IN plasticity may impact different domains of cognition in NDDs and memory loss in aging and AD. The development of new therapeutics for NDDs is critically dependent on a deep understanding of mechanisms by which risk genes impair cognition and cause seizures. Our prior and ongoing studies in the hippocampus and work by others in sensory cortices suggest that PV IN hypofunction and impaired feed-forward inhibition are hallmarks of ASD and other NDDs. Our discovery creates a pathway for mechanism-to-therapeutic intervention using gene therapy for individuals who harbor loss of function mutations in XPGs, many of which define rare diseases, and who exhibit seizures and intellectual disability. We hope that our ongoing AI+Bio efforts to engage XPGs using different therapeutic modalities will ultimately enable us design, engineer and harness PV IN cell states for cognitive restoration in brain disorders. Stay tuned.

Celebrating many milestones on this journey with the crew! Incredible group of scientists. Engaged and excited about discoveries even with the ongoing assault on science at all levels. @al0k_91 @TravisDGoode Yu-Tzu S, Jason A, Cinzia V, Iyanah M and Trey M not on X