# L-type Ca2+ Channel Spike Regulation of Spine Structural Plasticity and Excitation-Transcription Coupling

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2022 · $537,331

## Abstract

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).

## Key facts

- **NIH application ID:** 10380180
- **Project number:** 5R01MH123700-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** MARK L DELL'ACQUA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $537,331
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10380180

## Citation

> US National Institutes of Health, RePORTER application 10380180, L-type Ca2+ Channel Spike Regulation of Spine Structural Plasticity and Excitation-Transcription Coupling (5R01MH123700-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10380180. Licensed CC0.

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