During our life time, homeostatic signaling systems secure the integrity of neuronal circuits while allowing some flexibility that will be the basis for processes of cognition, learning and memory. It is therefore not surprising that a series of neurobiological diseases (autism spectrum disorder, Alzheimer's disease and schizophrenia, among them) have been linked to alterations in homeostatic mechanisms. Despite the tremendous importance of understanding neuronal homeostasis and how homeostatic signaling systems interact with neuronal plasticity, we know close to nothing about the molecular mechanisms underlying synaptic homeostasis. We have recently discovered that the highly conserved BK-type K+ channel, slowpoke (slo) is essential to the homeostatic control of synaptic function. This study will define a new function for slo while characterizing a new molecular mechanism for the homeostatic stabilization of neuronal function. In human, mutation in slo has been implicated in generalized epilepsy and paroxysmal dyskinesia, slo is also known to control the active properties of neurons and skeletal muscles, to be essential to aspects of synaptic plasticity and alcohol addiction, and to bind to really important signaling molecules, including Ca2+ channels. This study will combine quintal analysis of different mutant backgrounds, pharmacology, molecular genetics, biochemistry and activity dependent Ca2+ imaging using two-photon microscopy to show that (1)- the modification of Ca2+ influx is the mechanism at the heart of homeostatic plasticity and that this mechanism depends on presynaptic slo. (2)- Slo conductance is not required to perform this function;the Slo C-terminus tail is sufficient to restore homeostasis, illustrating a new essential function for the regulatory Slo sequences. (3)- the Slo C-terminus tail interacts with the Ca2+ channel responsible for neurotransmitter release, CaV2.1 (Cae). This interaction is required for the upregulation of Cae during synaptic homeostasis.

Public Health Relevance

This study identifies essential molecular players and a novel molecular mechanism for homeostasis. This mechanism will contribute to the understanding of addiction and plasticity, two processes in which slo is involved. In addition, because mutations in human slo result in epileptic seizures, this study will link failure in homeostatic compensation with epilepsy, opening a potential new avenue for therapeutic strategies.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Exploratory Grants (P20)
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Special Emphasis Panel (ZGM1-TWD-B)
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University of Puerto Rico Med Sciences
San Juan
United States
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Vaasjo, Lee O; Quintana, Alexandra M; Habib, Mohamed R et al. (2018) GABA-like immunoreactivity in Biomphalaria: Colocalization with tyrosine hydroxylase-like immunoreactivity in the feeding motor systems of panpulmonate snails. J Comp Neurol 526:1790-1805
Capó-Vélez, Coral M; Morales-Vargas, Bryan; García-González, Aurian et al. (2018) The alpha7-nicotinic receptor contributes to gp120-induced neurotoxicity: implications in HIV-associated neurocognitive disorders. Sci Rep 8:1829
Colón, Jennifer M; González, Pablo A; Cajigas, Ámbar et al. (2018) Continuous tamoxifen delivery improves locomotor recovery 6h after spinal cord injury by neuronal and glial mechanisms in male rats. Exp Neurol 299:109-121
Ferré, Sergi; Díaz-Ríos, Manuel; Salamone, John D et al. (2018) New Developments on the Adenosine Mechanisms of the Central Effects of Caffeine and Their Implications for Neuropsychiatric Disorders. J Caffeine Adenosine Res 8:121-131
Delgado-Vélez, Manuel; Lasalde-Dominicci, José A (2018) The Cholinergic Anti-Inflammatory Response and the Role of Macrophages in HIV-Induced Inflammation. Int J Mol Sci 19:
Rivera-Oliver, Marla; Moreno, Estefanía; Álvarez-Bagnarol, Yocasta et al. (2018) Adenosine A1-Dopamine D1 Receptor Heteromers Control the Excitability of the Spinal Motoneuron. Mol Neurobiol :
Capó-Vélez, Coral M; Delgado-Vélez, Manuel; Báez-Pagán, Carlos A et al. (2018) Nicotinic Acetylcholine Receptors in HIV: Possible Roles During HAND and Inflammation. Cell Mol Neurobiol :
Saxena, Manoj; Delgado, Yamixa; Sharma, Rohit Kumar et al. (2018) Inducing cell death in vitro in cancer cells by targeted delivery of cytochrome c via a transferrin conjugate. PLoS One 13:e0195542
Thapa, Bibek; Diaz-Diestra, Daysi; Santiago-Medina, Carlene et al. (2018) T1- and T2-weighted Magnetic Resonance Dual Contrast by Single Core Truncated Cubic Iron Oxide Nanoparticles with Abrupt Cellular Internalization and Immune Evasion. ACS Appl Bio Mater 1:79-89
Alicea, Daniel; Perez, Marizabeth; Maldonado, Carolina et al. (2017) Cortactin Is a Regulator of Activity-Dependent Synaptic Plasticity Controlled by Wingless. J Neurosci 37:2203-2215

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