Biology subjects

Herrlinger, S. A.

Publications and source records attributed to Herrlinger, S. A..

3 recordsLinked to original sources

bioRxiv2025

Rare mutations implicate CGE interneurons as a vulnerable axis of cognitive deficits across psychiatric disorders

Neuropsychiatric disorders such as autism spectrum disorder (ASD) and schizophrenia (SCZ) share genetic risk factors, including genes affected by rare high-penetrance single nucleotide variants (SNVs) and copy number variants (CNVs). ASD and SCZ exhibit both overlapping and distinct clinical phenotypes. Cognitive deficits and intellectual disability--critical predictors of long-term outcomes--are common to both conditions. To investigate shared and disorder-specific neurobiological impact of highly penetrant rare mutations in ASD and SCZ, we analyzed human single-nucleus whole-brain sequencing data to identify strongly affected brain cell types. Our analysis revealed caudal ganglionic eminence (CGE)-derived GABAergic interneurons as a key nexus for cognitive deficits across these disorders. Notably, genes within 22q11.2 deletions, known to confer a high risk for SCZ, ASD, and cognitive impairment, showed a strong expression bias toward vasoactive intestinal peptide-expressing cells (VIP+) among CGE subtypes. To explore perturbations of VIP+ GABAergic interneurons in the 22q11.2 deletion syndrome in vivo, we examined their activity in the Df(16)A+/- mouse model during a spatial navigation task and observed reduced activity along with altered responses to random rewards. At the population level, VIP+ interneurons exhibited impaired spatial encoding and diminished subtype-specific activity suggesting deficient disinhibition in CA1 microcircuits in the hippocampus, a region essential for learning and memory. Overall, these results demonstrate the crucial role of CGE-derived interneurons in mediating cognitive processes that are disrupted across a range of psychiatric and neurodevelopmental disorders.

neuroscience↗

bioRxiv2024

Disorganized Inhibitory Dynamics and Functional Connectivity in Hippocampal area CA1 of 22q11.2 Deletion Mutant Mice

Individuals with the 22q11.2 deletion syndrome, one of the strongest genetic risk factors for schizophrenia, demonstrate cognitive impairments, including episodic memory dysfunction. Place cell activity of excitatory pyramidal neurons in the hippocampus supporting episodic memory is impaired in a mouse model for the 22q11.2 deletion (Df(16)A+/-). While excitatory dynamics are under tight inhibitory control by multiple subtypes of GABAergic interneurons, previous studies have predominantly focused on a single subtype of PV-expressing interneurons; there have not yet been studies describing the functional relationships between molecularly identified inhibitory types in Df(16)A+/-mice. Here, we examined interneuron subtype-specific activity dynamics in the dorsal hippocampal area CA1 of Df(16)A+/- mice during random foraging and spatial reward navigation tasks. Capitalizing on 3D acousto-optical deflector two-photon microscopy with post hoc immunohistochemical identification, we found that multiple interneuron types exhibit aberrant responses to reward locations and delayed reward enrichment extinction. Df(16)A+/- inhibitory interneurons also carry markedly reduced spatial information in a subtype-dependent manner. We observed task-dependent changes in the correlation structure and coactivity among multiple GABAergic subtypes, suggesting a broadly disorganized microcircuit functionality in mutant mice. Overall, we identify widespread and heterogeneous subtype-specific alterations in interneuron dynamics during spatial reward navigation, reflecting impaired flexibility and organization in CA1 inhibitory microcircuits. Our study provides critical insights into how schizophrenia-risk mutations affect local-circuit interactions among diverse cell types in the mouse hippocampus during learning and spatial navigation.

neuroscience↗

bioRxiv2024

2P-NucTag: on-demand phototagging for molecular analysis of functionally identified cortical neurons

Neural circuits are characterized by genetically and functionally diverse cell types. A mechanistic understanding of circuit function is predicated on linking the genetic and physiological properties of individual neurons. However, it remains highly challenging to map the molecular properties onto functionally heterogeneous neuronal subtypes in mammalian cortical circuits in vivo. Here, we introduce a high-throughput two-photon nuclear phototagging (2P-NucTag) approach for on-demand and indelible labeling of single neurons via a photoactivatable red fluorescent protein following in vivo functional characterization in behaving mice. Using this novel function-forward pipeline to selectively label and transcriptionally profile previously inaccessible place and silent cells in the hippocampus of behaving mice, we identify unexpected differences in gene expression between these hippocampal pyramidal neurons with distinct spatial coding properties. Thus, 2P-NucTag opens a new way to uncover the molecular principles that govern the functional organization of neural circuits. One-Sentence Summary2P-NucTag - A novel high-throughput on-demand phototagging approach to identify selective gene expression of functionally distinct neurons in vivo in behaving animals.

neuroscience↗