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Principal Investigator: Jason C. Wester
Organization: OHIO STATE UNIVERSITY
Fiscal Year: 2024
Award: $368,747
Funding agency: National Institute of Mental Health
PROJECT SUMMARY/ABSTRACT
During brain development, neurons must properly differentiate into distinct subtypes to assemble healthy
circuits. Thus, disruption of this process can impact neural architecture and wiring, and contribute to disorders
such as autism, schizophrenia, and epilepsy. The hippocampus is a brain structure crucial for learning and
memory, and its function is compromised in these disorders. Excitatory pyramidal cells in area CA1 provide a
major output of hippocampal computations to other brain regions. These cells can be parsed based on their
physical position within CA1 as “deep” or “superficial.” Deep and superficial hippocampal pyramidal cells are
distinct classes of neurons that exhibit differential molecular signatures, electrophysiological properties,
sources of afferent input, and circuit connectivity with local inhibitory interneurons. Determining the
mechanisms underlying their differentiation is crucial for understanding hippocampal development and function
in both health and disease. Superficial pyramidal cells in CA1 preferentially express the transcriptional
regulator Satb2, which controls gene expression by modifying chromatin structure. In humans, mutations of
Satb2 cause developmental delay, intellectual disability, epilepsy, and autistic behaviors. Our preliminary data
show that knocking out Satb2 during early development in mice disrupts the differentiation of superficial
pyramidal cells in CA1. Furthermore, there are non-cell-autonomous changes to the migration and survival of
distinct subtypes of interneurons in mutant mice relative to controls. In the present proposal, three specific
aims will test the hypothesis that early expression of Satb2 is necessary for hippocampal pyramidal cell
differentiation and circuit development in CA1, while later expression is necessary to promote experience-
dependent synaptic plasticity. These experiments will use molecular genetic tools in mice to conditionally
knock out Satb2 from pyramidal cells during both early and late developmental stages. Aim 1 will use
electrophysiology and electrical stimulation to study the strength and plasticity of different sources of afferent
input to deep and superficial CA1 pyramidal cells in acute slices. This aim will test the hypothesis that early
Satb2 expression is necessary to establish differences in afferent input strength, while later expression is
necessary for activity-driven synaptic plasticity of these inputs. Aim 2 will use paired whole-cell recordings
between pyramidal cells (deep and superficial) and identified subtypes of interneurons to map circuits and
study details of their synaptic physiology. This aim will test the hypothesis that early Satb2 expression is
necessary to establish circuit motifs between local inhibitory interneurons and superficial pyramidal cells, while
later expression is necessary to recruit new inhibitory synapses in response to environmental enrichment. Aim
3 will use single-cell RNA-seq and ATAC-seq to determine how Satb2 knockout alters gene expression and
chromatin accessibility in CA1 at multiple developmental timepoints. This aim will provide molecular insight into
how Satb2 controls gene expression in CA1 through development, and how its function may change over time.
Terms: <21+ years old><ASD><ATAC sequencing><ATAC-seq><ATACseq><Acute><Adolescent><Adolescent Youth><Adult><Adult Human><Ammon Horn><Architecture><Area><Assay for Transposase-Accessible Chromatin using sequencing><Autism><Autistic Disorder><Birth><Brain><Brain Nervous System><Brain region><Cell Body><Cell Differentiation><Cell Differentiation process><Cells><Chromatin><Chromatin Structure><Classification><Connector Neuron><Cornu Ammonis><Data><Development><Developmental Delay><Developmental Delay Disorders><Differential Gene Expression><Disease><Disorder><E-stim><Early Infantile Autism><Electric Stimulation><Electrophysiology><Electrophysiology (science)><Embryo><Embryonic><Encephalon><Engineering / Architecture><Entorhinal Area><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epilepsy><Epileptic Seizures><Epileptics><Exhibits><Experimental Designs><Gene Expression><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profiling><Gene Transcription><Genes><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Health><Hippocampus><Human><Impairment><Infantile Autism><Inhibitory Synapse><Intellectual disability><Intellectual functioning disability><Intellectual limitation><Intercalary Neuron><Intercalated Neurons><Interneurons><Internuncial Cell><Internuncial Neuron><Kanner's Syndrome><Knock-out><Knockout><Knowledge><Learning><Location><Long-Term Potentiation><Longterm Potentiation><Maintenance><Maps><Mediating><Membrane><Memory><Mice><Mice Mammals><Modern Man><Modification><Molecular><Molecular Fingerprinting><Molecular Genetics><Molecular Profiling><Morphology><Murine><Mus><Mutant Strains Mice><Mutation><Nerve Cells><Nerve Unit><Neural Cell><Neural Development><Neurocyte><Neuronal Differentiation><Neurons><Neurophysiology / Electrophysiology><Osteoblasts><Output><Parturition><Physiology><Play><Position><Positioning Attribute><Process><Property><Proteins><Pyramidal Cells><RNA Expression><Radial><Radius><Regulatory Pathway><Risk-associated variant><Role><Schizophrenia><Schizophrenic Disorders><Seizure Disorder><Series><Slice><Source><Specific Child Development Disorders><Specific qualifier value><Specified><Structure><Synapses><Synaptic><Synaptic plasticity><Systematics><Techniques><Testing><Time><Tissue-Specific Differential Gene Expression><Tissue-Specific Gene Expression><Transcript Expression Analyses><Transcript Expression Analysis><Transcription><Transcription Regulation><Transcriptional Control><Transcriptional Regulation><Whole-Cell Recordings><Work><adulthood><analyze gene expression><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><autism spectral disorder><autism spectrum disorder><autistic behavior><autistic behaviour><autistic spectrum disorder><autistic-like behavior><cellular differentiation><chromatin remodeling><conditional knock-out><conditional knockout><craniofacial><craniofacies><dementia praecox><developmental><disease risk><disorder risk><electrophysiological><electrostimulation><entorhinal cortex><environment enrichment><environment enrichment for laboratory animals><environmental enrichment><environmental enrichment for laboratory animals><epigenetic regulation><epigenetically><epilepsia><epileptogenic><experience><experiment><experimental research><experimental study><experiments><gene expression analysis><gene expression assay><genome mutation><hippocampal><human disease><insight><intellectual and developmental disability><juvenile><juvenile human><limited intellectual functioning><membrane structure><memory consolidation><migration><molecular profile><molecular signature><mouse mutant><neocortical><neural><neural circuit><neural circuitry><neurocircuitry><neurodevelopment><neuron development><neuronal><neuronal development><new approaches><novel approaches><novel strategies><novel strategy><post-natal development><postnatal development><recruit><response><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><scRNA-seq><schizophrenic><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><synapse><synaptic circuit><synaptic circuitry><tool><transcriptional profiling>