The proposed studies focus on molecular mechanisms of signaling pathway modulation of excitability in neurons of immature hippocampus. Signaling cascades activate protein kinases, which biochemically modify substrate proteins via phosphorylation. Kinase phosphorylation of ion channel subunits is a well- characterized means of regulating channel function in neurons and therefore, membrane excitability. Despite these insights, the molecular mechanisms underlying the regulation of the membrane properties of immature neurons remain unclear. We propose that an important locus for mediating neuromodulation of excitability of neurons from immature hippocampus is through regulation of potassium (K+) channel activity by phosphorylation. This proposal focuses on Ca2+-activated K+ channels known as the small conductance SK channels. These subunits contribute to a component of the current known as the afterhyperpolarization (AHP). The AHP follows a single action potential or a series of action potentials. Therefore, the AHP plays a critical role in shaping the electrical responsiveness of hippocampal neurons beginning early in life, and modulation of this current can dramatically affect neuronal excitability. Given that K+ channels are critical to the regulation of neuronal excitability, developmental differences in K+ channel expression and kinase regulation may play a role in normal plasticity and pathological processes such as epilepsy in the immature brain. For these studies we will focus on SK2 and the current that it underlies, the apamin-sensitive AHP. The central hypothesis of this proposal is that the cAMP-dependent protein kinase (PKA) pathway regulates SK2 channel function through direct phosphorylation and that this post-translational mechanism as well as the developmental regulation of the expression of SK2 channels and the underlying mAHP contributes to the regulation of neuronal excitability in developing hippocampus. As part of our studies we will investigate the possibility that there are developmental differences in the expression and regulation of SK2 channel subunits and the apamin-sensitive AHP that may underlie the well-characterized observation that immature brain exhibits periods of increased excitability. This feature likely contributes to normal plasticity in developing CNS as well as pathology, such as increased seizure susceptibility in immature brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS049427-01A2
Application #
7034223
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Jacobs, Margaret
Project Start
2005-12-05
Project End
2010-11-30
Budget Start
2005-12-05
Budget End
2006-11-30
Support Year
1
Fiscal Year
2006
Total Cost
$337,500
Indirect Cost
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Patil, Vinit V; Guzman, Miguel; Carter, Angela N et al. (2016) Activation of extracellular regulated kinase and mechanistic target of rapamycin pathway in focal cortical dysplasia. Neuropathology 36:146-56
Sierra, Amanda; Martín-Suárez, Soraya; Valcárcel-Martín, Roberto et al. (2015) Neuronal hyperactivity accelerates depletion of neural stem cells and impairs hippocampal neurogenesis. Cell Stem Cell 16:488-503
Lugo, Joaquin N; Swann, John W; Anderson, Anne E (2014) Early-life seizures result in deficits in social behavior and learning. Exp Neurol 256:74-80
Brewster, Amy L; Lugo, Joaquin N; Patil, Vinit V et al. (2013) Rapamycin reverses status epilepticus-induced memory deficits and dendritic damage. PLoS One 8:e57808
Kazdoba, Tatiana M; Sunnen, C Nicole; Crowell, Beth et al. (2012) Development and characterization of NEX- Pten, a novel forebrain excitatory neuron-specific knockout mouse. Dev Neurosci 34:198-209
Marcelin, Béatrice; Lugo, Joaquin N; Brewster, Amy L et al. (2012) Differential dorso-ventral distributions of Kv4.2 and HCN proteins confer distinct integrative properties to hippocampal CA1 pyramidal cell distal dendrites. J Biol Chem 287:17656-61
Lugo, Joaquin N; Brewster, Amy L; Spencer, Corinne M et al. (2012) Kv4.2 knockout mice have hippocampal-dependent learning and memory deficits. Learn Mem 19:182-9
Sunnen, C Nicole; Brewster, Amy L; Lugo, Joaquin N et al. (2011) Inhibition of the mammalian target of rapamycin blocks epilepsy progression in NS-Pten conditional knockout mice. Epilepsia 52:2065-75
Barnwell, L Forbes S; Lugo, Joaquin N; Lee, Wai L et al. (2009) Kv4.2 knockout mice demonstrate increased susceptibility to convulsant stimulation. Epilepsia 50:1741-51
Ljungberg, M Cecilia; Sunnen, C Nicole; Lugo, Joaquin N et al. (2009) Rapamycin suppresses seizures and neuronal hypertrophy in a mouse model of cortical dysplasia. Dis Model Mech 2:389-98

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