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Principal Investigator: MARK L DELL'ACQUA
Organization: UNIVERSITY OF COLORADO DENVER
Fiscal Year: 2024
Award: $565,359
Funding agency: National Institute of Mental Health
Plasticity in the hippocampus leads to persistent changes in synaptic structure and function that
underlie learning and memory. Intracellular Ca2+ signaling pathways activated downstream of NMDA receptors
(NMDAR) and L-type voltage-gated Ca2+ channels (LTCC) contribute to changes synaptic function that are
required for initial expression of plasticity as well as changes in gene expression that support long-term
maintenance of plasticity. In particular, activation of LTCCs plays a key role in dendritic spine structural
plasticity and excitation-transcription (E-T) coupling to control the activity of transcription factors in the nucleus,
such as cAMP/Ca2+-response element binding protein (CREB), nuclear factor of activated T-cells (NFAT), and
myocyte enhancer factor 2 (MEF2). Alterations in LTCC function have been linked to multiple neurological and
neuropsychiatric diseases. Importantly, NFAT-dependent transcription may control the expression of a number
of target genes that play key roles in regulating E/I balance and excitability, including GABAA-Rs and voltage-gated potassium (Kv) channels. Our previous work established the scaffold protein AKAP79/150, which
anchors the cAMP-dependent kinase PKA and the Ca2+-dependent phosphatase calcineurin (CaN) near
LTCCs, as an essential regulator of E-T coupling via CaN-mediated dephosphorylation of NFAT. However,
due to the large distances between synapses in dendrites and the nucleus in the soma, neurons face unique
challenges in converting synaptic input into biochemical signals that control transcription. We recently found
that LTP stimulated NMDAR-LTCC-NFAT synapse-to-nucleus signaling utilizes dendritic Ca2+ spike
propagation to the soma as a novel E-T coupling mechanism. In addition, we found that this NMDAR-LTCC
activation during LTP induction promotes Ca2+-induced Ca2+ release in dendrites that engages the
endoplasmic reticulum (ER) Ca2+ sensor STIM1 to trigger negative-feedback regulation of LTCC Ca2+ influx
while also mediating novel structural plasticity of the dendritic spine ER. However, there are still critical gaps in
our knowledge regarding how NMDARs, LTCCs, and STIM1 operate over different spatial and temporal scales
to control both local dendritic structural plasticity and distal dendrite-to-soma spike propagation to regulate
transcription. Furthermore, we do not understand how the transcription of specific activity-regulated target
genes is controlled by different patterns of activity transduced by these mechanisms to modulate key aspects
of neuronal function, such as E/I balance. Thus, here we propose research to fill these gaps by characterizing
the roles of postsynaptic LTCC Ca2+ signaling in mediating local structural plasticity in dendrites and Ca2+ spike
relay from dendrites to soma (aim 1) in control gene of expression through NFAT and its co-regulators to
impact E/I balance (aim 2).
Terms: <3'5'-cyclic ester of AMP><A kinase anchoring protein><AD dementia><AD/HD><ADHD><AKAP><AP-1><AP-1 Enhancer-Binding Protein><AP1><AP1 protein><ASD><ATP-protein phosphotransferase><Activator Protein-1><Adenosine Cyclic 3',5'-Monophosphate><Adenosine Cyclic Monophosphate><Adenosine Cyclic Monophosphate-Dependent Protein Kinases><Adenosine, cyclic 3',5'-(hydrogen phosphate)><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimers Dementia><Ammon Horn><Attention deficit hyperactivity disorder><Autism><Autistic Disorder><Basal Transcription Factor><Basal transcription factor genes><Binding Proteins><Biochemical><Bipolar Affective Psychosis><Bipolar Disorder><Brain><Brain Nervous System><CNS plasticity><Calcineurin><Calcium Channel><Calcium Channel Antagonist Receptor><Calcium Channel Blocker Receptors><Calcium Ion Channels><Calcium ion><Cell Communication and Signaling><Cell Nucleus><Cell Signaling><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Complex><Cornu Ammonis><Coupling><Cyclic AMP><Cyclic AMP-Dependent Protein Kinases><Degenerative Neurologic Disorders><Dendrites><Dendritic Spines><Dephosphorylation><Distal><Disturbance in cognition><Down's Syndrome><Early Infantile Autism><Encephalon><Endoplasmic Reticulum><Enhancer-Binding Protein AP1><Equilibrium><Ergastoplasm><Excitatory Synapse><Face><Feedback><Gene Expression><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Transcription><Glutamate Receptor><Glutamates><Hippocampus><Human><Impaired cognition><Infantile Autism><Intellectual disability><Intellectual functioning disability><Intellectual limitation><Intracellular Communication and Signaling><K element><Kanner's Syndrome><Kinase Family Gene><Kinases><Knowledge><L-Glutamate><Langdon Down syndrome><Lead><Learning><Ligand Binding Protein><Ligand Binding Protein Gene><Link><Long-Term Potentiation><Longterm Potentiation><MEF-2><Maintenance><Major Depressive Disorder><Manic-Depressive Psychosis><Mediating><Memory><Mental Depression><Modern Man><Molecular><Mongolism><N Methyl D aspartic Acid><N methyl D aspartate><N-Methyl-D-Aspartate Receptors><N-Methyl-D-aspartate><N-Methylaspartate><N-Methylaspartate Receptors><NF-AT><NF-AT proteins><NFAT proteins><NFAT-1><NFATC proteins><NMDA><NMDA Receptor-Ionophore Complex><NMDA Receptors><Nerve Cells><Nerve Unit><Nervous System Degenerative Diseases><Nervous System Diseases><Nervous System Disorder><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neurologic Disorders><Neurological Disorders><Neuronal Plasticity><Neurons><Nucleus><PKA><PP2B><Pathway interactions><Pattern><Pb element><Phosphatases><Phosphohydrolases><Phosphomonoesterases><Phosphoric Monoester Hydrolases><Phosphotransferase Gene><Phosphotransferases><Play><Potassium><Predominantly Hyperactive-Impulsive Type Attention-Deficit Disorder><Predominantly Hyperactive-Impulsive Type Hyperactivity Disorder><Primary Senile Degenerative Dementia><Process><Protein Binding><Protein Dephosphorylation><Protein Kinase><Protein Kinase A><Protein Phosphatase-2B><Proteins><RNA Expression><Receptor Activation><Receptor Protein><Regulation><Research><Response Elements><Rodent><Rodentia><Rodents Mammals><Role><STIM1><STIM1 gene><Scaffolding Protein><Schizophrenia><Schizophrenic Disorders><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Molecule><Spinal Column><Spine><Stromal Interaction Molecule 1><Structure><Synapses><Synaptic><Synaptic plasticity><Transcription><Transcription Factor AP-1><Transcription Factor Proto-Oncogene><Transcription Regulation><Transcription factor genes><Transcriptional Control><Transcriptional Regulation><Transphosphorylases><Trisomy 21><VDCC><Vertebral column><Voltage-Dependent Calcium Channels><Work><adenosine 3'5' monophosphate><autism spectral disorder><autism spectrum disorder><autistic spectrum disorder><backbone><balance><balance function><biological signal transduction><bipolar affective disorder><bipolar disease><bipolar illness><bipolar mood disorder><bound protein><cAMP><cAMP-Dependent Protein Kinases><calcineurin phosphatase><central nervous system plasticity><chromosome 21 trisomy syndrome><clinical depression><cognitive dysfunction><cognitive loss><congenital acromicria syndrome><cytoplasmic nuclear factor of activated T-cells><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><dementia praecox><dendrite spine><depression><faces><facial><glutamatergic><glycogen synthase a kinase><heavy metal Pb><heavy metal lead><hippocampal><hydroxyalkyl protein kinase><intellectual and developmental disability><limited intellectual functioning><major depression><major depression disorder><manic depressive disorder><manic depressive illness><mef2 protein><morbus Down><muscle-specific enhancer factor-2><myocyte enhancer factor 2><myocyte-specific enhancer-binding factor 2><neural cell body><neural plasticity><neurodegenerative illness><neurological disease><neuronal><neuronal cell body><neuroplastic><neuroplasticity><neuropsychiatric disease><neuropsychiatric disorder><novel><nuclear factors of activated T-cells><pathway><phosphorylase b kinase kinase><postsynaptic><primary degenerative dementia><pseudohypertrophic progressive muscular dystrophy><receptor><response><schizophrenic><senile dementia of the Alzheimer type><sensor><social role><soma><synapse><synapse function><synaptic function><transcription factor><transcription factor NF-AT><trisomy 21 syndrome><voltage>