Gene-Environment Interaction in a Conditional NMDAR-Knockout Model of Schizophrenia

Interactions between genetic and environmental risk factors take center stage in the pathology of schizophrenia. We assessed if the stressor of reduced environmental enrichment applied in adulthood provokes deficits in the positive, negative or cognitive symptom domains of schizophrenia in a mouse line modeling NMDA-receptor (NMDAR) hypofunction in forebrain inhibitory interneurons (Grin1ΔPpp1r2). We find that Grin1ΔPpp1r2 mice, when group-housed in highly enriched cages, appear largely normal across a wide range of schizophrenia-related behavioral tests. However, they display various short-term memory deficits when exposed to minimal enrichment. This demonstrates that the interaction between risk genes causing NMDA-receptor hypofunction and environmental risk factors may negatively impact cognition later in life

Sparse, decorrelated odor coding in the mushroom body enhances learned odor discrimination

Sparse coding may be a general strategy of neural systems for augmenting memory capacity. In Drosophila melanogaster, sparse odor coding by the Kenyon cells of the mushroom body is thought to generate a large number of precisely addressable locations for the storage of odor-specific memories. However, it remains untested how sparse coding relates to behavioral performance. Here we demonstrate that sparseness is controlled by a negative feedback circuit between Kenyon cells and the GABAergic anterior paired lateral (APL) neuron. Systematic activation and blockade of each leg of this feedback circuit showed that Kenyon cells activated APL and APL inhibited Kenyon cells. Disrupting the Kenyon cell–APL feedback loop decreased the sparseness of Kenyon cell odor responses, increased inter-odor correlations and prevented flies from learning to discriminate similar, but not dissimilar, odors. These results suggest that feedback inhibition suppresses Kenyon cell activity to maintain sparse, decorrelated odor coding and thus the odor specificity of memories

Btbd11 supports cell-type-specific synaptic function

Summary: Synapses in the brain exhibit cell-type-specific differences in basal synaptic transmission and plasticity. Here, we evaluated cell-type-specific specializations in the composition of glutamatergic synapses, identifying Btbd11 as an inhibitory interneuron-specific, synapse-enriched protein. Btbd11 is highly conserved across species and binds to core postsynaptic proteins, including Psd-95. Intriguingly, we show that Btbd11 can undergo liquid-liquid phase separation when expressed with Psd-95, supporting the idea that the glutamatergic postsynaptic density in synapses in inhibitory interneurons exists in a phase-separated state. Knockout of Btbd11 decreased glutamatergic signaling onto parvalbumin-positive interneurons. Further, both in vitro and in vivo, Btbd11 knockout disrupts network activity. At the behavioral level, Btbd11 knockout from interneurons alters exploratory behavior, measures of anxiety, and sensitizes mice to pharmacologically induced hyperactivity following NMDA receptor antagonist challenge. Our findings identify a cell-type-specific mechanism that supports glutamatergic synapse function in inhibitory interneurons—with implications for circuit function and animal behavior