Document text
Principal Investigator: Daniel Feldman
Organization: UNIVERSITY OF CALIFORNIA BERKELEY
Fiscal Year: 2024
Award: $373,403
Funding agency: National Institute of Neurological Disorders and Stroke
Summary
Inhibitory interneurons in cerebral cortex show rapid plasticity of intrinsic excitability in response to sensory
experience and learning. The molecular mechanisms and functions of such plasticity, and its potential role in
disease, are poorly understood. We study this in mouse somatosensory cortex (S1), where brief sensory
deprivation drives a rapid reduction in parvalbumin (PV) interneuron intrinsic excitability, which acts to
stabilize pyramidal cell firing rates. We recently found similar plasticity in somatostatin (SST) interneurons,
suggesting that rapid intrinsic plasticity is a common property of MGE-derived interneurons. Here, we
characterize the mechanisms for intrinsic plasticity in interneurons, and test the novel hypothesis that deficits
in this process play a major role in inhibitory circuit dysfunction in autism.
In Aim 1, we identify the molecular signaling pathways that mediate intrinsic plasticity in PV neurons
induced by brief sensory deprivation. Prior work shows that deprivation rapidly increases Kv1 potassium
currents, which elevates PV spike threshold. We will identify the molecular pathways for this plasticity, using
a combination of immunohistochemistry and qHCR-FISH to detect alterations in protein and gene expression,
and pharmacological and genetic tools to test causal involvement of candidate signaling pathways. We focus
on candidate pathways that are known to regulate Kv1.1 channels. We also use single-nucleus RNAseq for
unbiased discovery of regulated genes. Preliminary results implicate the Er81-KCNA1 pathway, which drives
increased expression of Kv1.1. This work will yield molecular understanding and molecular markers of PV
intrinsic plasticity, which we will use to characterize its prevalence and properties.
Aim 2 tests the novel hypothesis that deficits in PV intrinsic plasticity are the underlying cause of PV
circuit dysfunction in some genetic forms of autism, specifically for autism genes that regulate activity-
dependent gene expression and/or Kv1.1 function in PV cells. We propose that due to loss of PV intrinsic
plasticity, neural coding is destabilized in autism. We will test this hypothesis in Fmr1, Tsc2, and Cntnap2
transgenic mouse models of autism. As part of this work, we will test whether restoring gene expression
selectively in PV cells rescues PV intrinsic plasticity and stabilizes pyramidal cell coding. If so, this would
suggest a new therapeutic approach to autism in restoration of PV intrinsic excitability.
Aim 3 tests for plasticity in SST circuits, which is little studied. In preliminary data, deprivation alters
SST intrinsic excitability and other aspects of SST circuit function. This demonstrates that SST plasticity
exists. We will characterize SST circuit plasticity and identify molecular mechanisms for SST intrinsic
plasticity, to test for possible common mechanisms with PV intrinsic plasticity. Together, this grant will
develop and test the novel hypothesis that plasticity of intrinsic excitability is a major form of plasticity in PV
and SST interneurons that plays important roles in regulating cortical function and disease.
Terms: <ASD><Affect><Autism><Autistic Disorder><Autoregulation><BDNF><Basic Research><Basic Science><Brain-Derived Neurotrophic Factor><Cell Body><Cell Communication and Signaling><Cell Nucleus><Cell Signaling><Cells><Cerebral cortex><Code><Coding System><Connector Neuron><Cyclic Somatostatin><D Cells><Data><Delta Cell><Dependence><Disease><Disorder><Dysfunction><Early Infantile Autism><ErbB-4><ErbB4><ErbB4 gene><FMR-1 Protein><FMR1 Protein><FMR1 gene><FMRP><FMRP protein><FRAXA><Failure><Fragile X Mental Retardation 1 Gene><Fragile X Mental Retardation Protein><Functional disorder><GGF><GGF2><Gene Action Regulation><Gene Alteration><Gene Expression><Gene Expression Regulation><Gene Mutation><Gene Regulation><Gene Regulation Process><Genes><Genetic><Grant><Growth Hormone Inhibiting Factors><Growth Hormone-Inhibiting Hormone><HER-4><HER4><HGL><HRGA><Heregulin Gene><Homeostasis><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Impairment><Induced Neurons><Infantile Autism><Intercalary Neuron><Intercalated Neurons><Interneurons><Internuncial Cell><Internuncial Neuron><Intracellular Communication and Signaling><K element><Kanner's Syndrome><Learning><Mediating><Messenger RNA><Mice><Mice Mammals><Molecular><Murine><Mus><NDF/Heregulin Receptor Gene><NEU Differentiation Factor Gene><NRG1><NRG1 gene><NRG3><NRG3 gene><Nerve Cells><Nerve Unit><Neural Cell><Neuregulin 3><Neurocyte><Neurons><Nucleus><Output><Parvalbumins><Pathway interactions><Pharmacology><Physiological Homeostasis><Physiology><Physiopathology><Play><Potassium><Prevalence><Process><Property><Proteins><Pyramidal Cells><RNA Seq><RNA sequencing><RNAseq><Regulation><Role><SRIH><SRIH-14><Sensory><Sensory Deprivation><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Single-Nucleus Sequencing><Somatosensory Cortex><Somatostatin><Somatostatin Cells><Somatostatin Secreting Cell><Somatostatin-14><Somatotropin Release Inhibiting Factors><Somatotropin Release-Inhibiting Hormone><Structure><Techniques><Testing><Transcription Regulation><Transcriptional Control><Transcriptional Regulation><Transgenic Mice><Vibrissae><Whiskers><Work><autism model><autism spectral disorder><autism spectrum disorder><autistic spectrum disorder><biological signal transduction><critical period><deprivation><experience><fragile X FMR1 protein><fragile X mental retardation 1><fragile X mental retardation-1 protein><growth hormone release inhibiting factor><iNeuron><mRNA><model of autism spectrum disorder><molecular biomarker><molecular marker><mouse model><murine model><neural><neuronal><new drug target><new druggable target><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapy approach><novel therapy target><pathophysiology><pathway><pharmacologic><protein expression><response><restoration><sNuc-Seq><selective expression><selectively expressed><sensory cortex><single nucleus RNA-sequencing><single nucleus seq><single-nucleus RNA-seq><snRNA sequencing><snRNA-seq><social role><somesthetic sensory cortex><tool><transcriptome sequencing><transcriptomic sequencing><voltage><voltage clamp>