FXR1 regulation of parvalbumin interneurons in the prefrontal cortex is critical for schizophrenia-like behaviors.

Parvalbumin interneurons (PVIs) are affected in many psychiatric disorders including schizophrenia (SCZ), however the mechanism remains unclear. FXR1, a high confident risk gene for SCZ, is indispensable but its role in the brain is largely unknown. We show that deleting FXR1 from PVIs of medial prefrontal cortex (mPFC) leads to reduced PVI excitability, impaired mPFC gamma oscillation, and SCZ-like behaviors. PVI-specific translational profiling reveals that FXR1 regulates the expression of Cacna1h/Cav3.2 a T-type calcium channel implicated in autism and epilepsy. Inhibition of Cav3.2 in PVIs of mPFC phenocopies whereas elevation of Cav3.2 in PVIs of mPFC rescues behavioral deficits resulted from FXR1 deficiency. Stimulation of PVIs using a gamma oscillation-enhancing light flicker rescues behavioral abnormalities caused by FXR1 deficiency in PVIs. This work unveils the function of a newly identified SCZ risk gene in SCZ-relevant neurons and identifies a therapeutic target and a potential noninvasive treatment for psychiatric disorders.

Metasurface-Enhanced Mid-Infrared Spectrochemical Imaging of Tissues.

Label-free and nondestructive mid-infrared vibrational hyperspectral imaging is an essential tissue analysis tool, providing spatially resolved biochemical information critical to understanding physiological and pathological processes. However, the chemically complex and spatially heterogeneous composition of tissue specimens and the inherently weak interaction of infrared light with biomolecules limit the analytical performance of infrared absorption spectroscopy. Here, an advanced mid-infrared spectrochemical tissue imaging modality is introduced using metasurfaces that support strong surface-localized electromagnetic fields to capture quantitative molecular maps of large-area murine brain tissue sections. The approach leverages polarization-multiplexed multi-resonance plasmonic metasurfaces to simultaneously detect various functional biomolecules. The surface-enhanced mid-infrared spectral imaging method eliminates the non-specific effects of bulk tissue morphology on quantitative spectral analysis and improves chemical selectivity. This study shows that metasurface enhancement increases the retrieval of amide I and II bands associated with protein secondary structures. Moreover, it is demonstrated that plasmonic metasurfaces enhance the chemical contrast in infrared images and enable detection of ultrathin tissue regions that are not otherwise visible to conventional mid-infrared spectral imaging. While this work uses murine brain tissue sections, the chemical imaging method is well-suited for other tissue types, which broadens its potential impact for translational research and clinical histopathology.

Elevated levels of FMRP-target MAP1B impair human and mouse neuronal development and mouse social behaviors via autophagy pathway.

Fragile X messenger ribonucleoprotein 1 protein (FMRP) binds many mRNA targets in the brain. The contribution of these targets to fragile X syndrome (FXS) and related autism spectrum disorder (ASD) remains unclear. Here, we show that FMRP deficiency leads to elevated microtubule-associated protein 1B (MAP1B) in developing human and non-human primate cortical neurons. Targeted MAP1B gene activation in healthy human neurons or MAP1B gene triplication in ASD patient-derived neurons inhibit morphological and physiological maturation. Activation of Map1b in adult male mouse prefrontal cortex excitatory neurons impairs social behaviors. We show that elevated MAP1B sequesters components of autophagy and reduces autophagosome formation. Both MAP1B knockdown and autophagy activation rescue deficits of both ASD and FXS patients' neurons and FMRP-deficient neurons in ex vivo human brain tissue. Our study demonstrates conserved FMRP regulation of MAP1B in primate neurons and establishes a causal link between MAP1B elevation and deficits of FXS and ASD.