Document text
Principal Investigator: Nour Al-muhtasib
Organization: YALE UNIVERSITY
Fiscal Year: 2019
Award: $61,226
Funding agency: National Institute of Neurological Disorders and Stroke
The overall goal of this proposal is to investigate the role of endocannabinoid (ECB) signaling in
regulating distinct cortical inhibitory synapses. Physiological brain development and function are
dependent on a fine-tuned balance of synaptic excitation and inhibition. As such, dysregulation of inhibition has
been implicated in a variety of neurodevelopmental disorders. The cellular targets and consequences of
GABAergic signaling in adult animals is well understood, however the specific interneurons modulated by
ECB signaling remains poorly studied. Cortical inhibition is mediated by a diverse group of GABAergic
interneurons (INs), including cells co-expressing the calcium binding protein parvalbumin (PV), the peptide
transmitter somatostatin (SOM), or the serotonin 5HT3a receptor. Cortical INs differ in their synaptic targets,
with PV-INs making synapses onto the perisomatic and proximal dendritic regions of target pyramidal neurons
and SOM-INs making connections onto the dendritic arbors. A subset of 5HT3a-INs which express the
vasoactive intestinal peptide (VIP), innervate dendrites of pyramidal neurons and other interneurons. This
subcellular localization allows PV-INs to regulate the magnitude and timing of PN spike output and SOM-INs to
regulate dendritic spine and shaft calcium influx along with glutamatergic synaptic plasticity. While the birth and
migration of GABAergic INs is well understood, there remain gaps in our knowledge of the molecular and
cellular mechanisms that influence inhibitory signaling. ECBs influence synaptogenesis and long-term plasticity
of both excitatory and inhibitory connections. Although data has shown coexpression of the cannabinoid type-1
(CB1) receptor with SOM or VIP, colocalization of the CB1 receptor within the various interneurons has not
been studied and will be addressed in this proposal. ECB release in the cortex modulates presynaptic GABA
release and can drive both short- and long-term depression of inhibitory transmission, however the identity of
the presynaptic INs sensitive to ECB activity is not well-characterized. Moreover, the consequences of CB1
receptor loss from distinct interneurons is unknown. In this proposal, we seek to determine how ECB signaling
modulates GABAergic signaling mediated by distinct IN populations. We hypothesize that ECB signaling
modulates cortical activity, with a key role in influencing plasticity mediated by dendritic targeting
interneurons. We propose a novel combination of tools including electrophysiology, 2-photon laser-scanning
microscopy (2PLSM), and optogenetic stimulation of genetically-targeted INs in the mouse primary visual
cortex. Our experiments will provide an unprecedented level of insight into the development of GABAergic
circuits in the neocortex.
Terms: <2-photon><4-Aminobutanoic Acid><4-Aminobutyric Acid><4-amino-butanoic acid><5-HT><5-Hydroxytryptamine><5HT><Address><Aminalon><Aminalone><Ammon Horn><Autism><Autistic Disorder><Automobile Driving><Birth><Brain><Brain Nervous System><CB1><CB1 Receptor><CB1R><CNR1 gene><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Calcium><Calcium-Binding Proteins><Cannabinoid Receptor CB1><Cas nuclease technology><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Connector Neuron><Cornu Ammonis><Cyclic Somatostatin><Data><Dendrites><Dendritic Spines><Development><Disease model><Drug Therapy><Dysfunction><ECB signaling><Early Infantile Autism><Electrophysiology><Electrophysiology (science)><Encephalon><Endocannabinoids><Endogenous Cannabinoids><Enteramine><Epilepsy><Epileptic Seizures><Epileptics><Equilibrium><Experimental Therapies><Functional disorder><GABA><Glutamates><Goals><Growth Hormone Inhibiting Factors><Growth Hormone-Inhibiting Hormone><Hippocampus><Hippocampus (Brain)><Hippophaine><In Situ Hybridization><Infantile Autism><Inhibitory Synapse><Intercalary Neuron><Intercalated Neurons><Interneurons><Internuncial Cell><Internuncial Neuron><Intracellular Communication and Signaling><Investigational Therapies><Investigational Treatments><Kanner's Syndrome><Knowledge><L-Glutamate><Laser Scanning Microscopy><Lead><Long-Term Depression><Long-Term Synaptic Depression><LoxP-flanked allele><Mediating><Mental disorders><Mental health disorders><Mice><Mice Mammals><Molecular><Murine><Mus><Neocortex><Nerve Cells><Nerve Unit><Nervous System Diseases><Neural Cell><Neurocyte><Neurodevelopmental Disorder><Neurologic Disorders><Neurological Development Disorder><Neurological Disorders><Neurons><Neuropeptides><Neurophysiology / Electrophysiology><Output><PHM27><Parturition><Parvalbumins><Pathway interactions><Pb element><Peptides><Pharmacology><Pharmacotherapy><Physiologic><Physiological><Physiopathology><Play><Population><Primary visual cortex><Psychiatric Disease><Psychiatric Disorder><Pyramidal neuron><Receptor Protein><Regulation><Research><Role><SRIH><SRIH-14><Schizophrenia><Schizophrenic Disorders><Seizure Disorder><Serotonin><Signal Transduction><Signal Transduction Systems><Signaling><Somatostatin><Somatostatin-14><Somatotropin Release Inhibiting Factors><Somatotropin Release-Inhibiting Hormone><Striate Cortex><Striate area><Structure><Synapses><Synaptic><Synaptic plasticity><Transgenic Mice><Transmission><Vasoactive Intestinal Peptide><Vasoactive Intestinal Polypeptide><Vasointestinal Peptide><Viral><adult animal><area striata><autism spectrum disorder><autistic spectrum disorder><balance><balance function><biological signal transduction><cannabinoid receptor 1><cannabinoid receptor type 1><cell type><cellular targeting><dementia praecox><dendrite spine><developmental><disorder model><driving><drug treatment><electrophysiological><endocannabinoid signaling><epilepsia><epileptiform><epileptogenic><experiment><experimental research><experimental study><experimental therapeutic agents><experimental therapeutics><floxed><floxed allele><gamma-Aminobutyric Acid><glutamatergic><growth hormone release inhibiting factor><heavy metal Pb><heavy metal lead><hippocampal><hippocampal pyramidal neuron><homotypical cortex><in situ Hybridization Genetics><in situ Hybridization Staining Method><innervation><insight><isocortex><longterm depression><longterm synaptic depression><mature animal><mental illness><migration><neopallium><nerve supply><nervous system disorder><neurological disease><neuronal><neuropsychiatric disease><neuropsychiatric disorder><novel><operation><optogenetics><pathophysiology><pathway><postsynaptic><presynaptic><psychiatric illness><psychological disorder><receptor><receptor expression><schizophrenic><social role><synapse><synapse formation><synaptic depression><synaptogenesis><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><tool><transmission process><two-photon><γ-Aminobutyric Acid>