ion channels; intrinsic excitability; neurophysiology; temporal coding; KCNMA1 channelopathy, an ultra-rare disorder characterized by neuromuscular dysfunction and dyskinesia, epilepsy, and neurodevelopmental delays
Andrea Meredith, Ph.D. joined NINDS in November 2024, as the Director of the Division of Extramural Activities (DEA). In this role, Dr. Meredith oversees the coordination of NINDS’s extramural program. She leads a team of eight branch chiefs, each playing a vital role in advancing the goals of the extramural program.
The Programmatic Operations Team oversees the receipt and referral of NINDS applications, development of new funding opportunities (NOFOs), administration of NINDS programs such as the R35 and RM1, and extramural process and programmatic analysis. The NINDS Council Team runs three NINDS Advisory Council meetings annually, where funding award decisions are finalized, and assists in the management of other Federal Advisory Committee Act (FACA)-related committee meetings. Funding awards for grants, cooperative agreements, contracts, and clinical trials are administered by the Grants Management Branch, which ensures award compliance with federal laws, regulations, and policies. The Office of Training and Workforce Development builds and supports the national neuroscience skill base and workforce infrastructure through a variety of specialized NINDS training programs. The Office of Research Quality and the Data Modeling and Analytics Team each house programs that underpin rigorous, high-quality scientific research, transparent reporting, data management, and AI initiatives.
Prior to joining NINDS, Dr. Meredith was a Professor of Physiology at the University of Maryland School of Medicine in Baltimore for more than two decades. She headed the KCNMA1 Translational Research Laboratory, an NIH-funded research lab focused on understanding a new neurogenetic disorder. Her research established the genetic curation, clinical manifestations, mechanistic underpinnings, and gene variant-delineated treatment for KCNMA1 Channelopathy, an ultra-rare seizure and dyskinesia disorder resulting from aberrant electrical signaling in the brain and muscles. She has authored over 60 peer-reviewed publications and co-founded the KCNMA1 International Advocacy Foundation (KCIAF). Dr. Meredith has also worked with clinical, NIH, industry, and patient partners to raise awareness of channelopathy disorders. She served on numerous NIH scientific review panels, scientific advisory boards, and patient advocacy committees and participated in many types of outreach activities that educate the public about brain health and neurological disorders.
Research Interests
Dr. Meredith studies how ion channels regulate information coding in dynamic systems by combining the genetic manipulation of ion channels with electrophysiology and in vivo brain and muscle physiology. The goal is to understand the ion channel biophysics behind neuromuscular function in animal models and humans.
BK Channels (KCNMA1)
The lab studies BK (Big K+) large conductance voltage and Ca2+-activated K+ channel. The BK channel pore-forming alpha subunit is encoded by a single gene (KCNMA1 in humans, or Slo/Slowpoke in mouse and flies, respectively). Like other Kv family members, BK channels are comprised of a tetramer of alpha subunits, modulatory beta (β1-4) and gamma subunits (ɣ1-4 or LRRC26, 52, 55, and 38), and are closely localized with intracellular Ca2+ sources such as voltage-gated Ca2+ channels and RyRs.
BK channels are the ‘King of Ion Channels’ based on several exceptional features, including their unusually large unitary conductance, allosteric voltage and Ca2+-dependent gating, and well-characterized biophysical properties. A variety of transgenic lines (Kcnma1N999S, Kcnma1D434G, Kcnma1H444Q, Kcnma1–/–, Tg-BKR207Q, and Kcnma1flox-tdTomato) was created to study BK channel function and pathophysiology, in systems ranging from circadian rhythm to cardiac rhythm, and motor function, urodynamics, reproductive function, neurovascular coupling, hearing, and human (KCNMA1 channelopathy) and animal (Ryegrass Staggers) neurological disease.
KCNMA1-Linked Channelopathy
KCNMA1-linked channelopathy is a rare new neurological disorder with less than 70 documented cases at present. Mutations in KCNMA1, the gene that encodes the pore-forming subunit of the BK channel, have been linked to seizures, paroxysmal dyskinesia, and other types of neuromuscular and neurological dysfunction. The lab studies how human genetic variation (pathological mutations and single nucleotide polymorphisms) influence neuronal firing patterns and brain and motor function. The goal is to understand how clinical symptoms are produced by the changes in BK channel activity associated with patient mutations. Patients and families can find out more about KCNMA1-linked channelopathy.
Circadian Regulation of Excitability
Circadian physiology is an ideal model system for studying information coding. Daily behavioral and physiological rhythms (~ 24 hrs) are a universal trait of animals, vital for adaptation to their environment and overall fitness. In mammals, lesion and transplantation studies have localized the principal circadian pacemaker to the suprachiasmatic nucleus (SCN) of the hypothalamus, identifying a discrete neural substrate for a complex behavior. A novel role was identified for the BK channel in the daily patterning of neural activity in the SCN. Kcnma1–/– mice have degraded circadian behavioral and physiological rhythms, and their SCN neurons exhibit aberrant daily action potential rhythms in the SCN circuit. The lab is studying the circadian regulation of BK current properties in SCN neurons and how specific properties of the BK current influence the neural representation of circadian time.
BK Channels in Cardiovascular Function
BK channels are directly implicated in cardiovascular function through their regulation of vascular tone. However, a role for BK channels in the heart itself had been mostly discounted based on the weak relative expression. It was discovered that several selective blockers of BK channels caused a counter-intuitive decrease in heart rate (bradycardia). BK antagonist-induced bradycardia was not observed in mice lacking BK channels (Kcnma1–/–), supporting a role for the channels in controlling heart rate and the confirming specificity of this effect.
Alternate Splicing of KCNMA1
BK channels are physiologically activated by voltage and Ca2+, modulating a diversity of membrane signals in different cells types. Even in excitable cells, such as neurons and muscle where they play prominent roles, their influence encompasses diverse roles in action potential repolarization, afterhyperpolarizations, repetitive firing, spontaneous firing, neurotransmitter release, plateau potentials, and baseline membrane potentials. BK channels have been extensively studied at the biophysical level, and these studies build on this work by discovering the impact of tissue-specific variation in BK current properties a specialized dynamic system, the circadian clock. By combining genetic manipulation of BK channels and cloning of native splice variants with cellular, circuit, and physiological recordings, novel systems are identified, such as the suprachiasmatic nucleus, where direct links between BK channel biophysical properties and neuronal and circuit excitability can be established.
Novel Roles for BK Channels
BK channels are widely, but specifically, expressed in both excitable (brain and muscle) and non-excitable tissues (kidney and bone). Overall, less is known about their roles in non-excitable cell types or intact physiological systems. Unlike the voltage-gated K+ channel family, there is only one gene that encodes the BK channel, and Kcnma1–/– mice display a surprising number of phenotypes at the cellular and systems levels. This lack of redundancy has enabled us to use the BK channel deletion mouse as a selective mechanism for perturbing signaling in a variety of pathways. Several transgenic mouse lines (Kcnma1–/–, Tg-BKR207Q, and Kcnma1flox-tdTomato) we made for studies that will identify new systems in which BK channels play dominant roles.
Imaging Circadian Rhythms in Intracellular Signaling in the Brain’s Clock Circuit
To understand how the time-of-day code is communicated from the brain’s clock to the body, new Brain Initiative-funded tools were created to track circadian rhythms in neural activity and intracellular signaling. Measuring the temporal and spatial dynamics across key signaling pathways requires coordinated observation of multiple networks within individual cells and multiple neurons within intact circuits. In collaboration with Megan Rizzo, the lab developed novel methodology for simultaneous optical imaging of multiple quantitative FRET biosensors within single neurons and circuits. These new FRET sensors were then used to track the rhythmic fluctuations in membrane and intracellular signaling.
Publications
KCNMA1 Channelopathy
Dinsdale RL and Meredith AL (2024). Evaluation of four KCNMA1 channelopathy variants on BK channel current under Cav1.2 activation. Channels 18(1):2396346.
Meredith AL (2024). BK Channelopathies and KCNMA1-Linked Disease Models. Annual Reviews in Physiology 86(1): 277-300.
Moldenhauer HJ, Tammen K, and Meredith AL (2024). Structural mapping of patient-associated KCNMA1 gene variants. Biophysical Journal 123 (14): P1984-2000
Park SM, Roache CE, Iffland PH, Moldenhauer HJ, Matychak KK, Plante AE, Lieberman AG, Crino PB, and Meredith AL (2022). BK channel properties correlate with neurobehavioral severity in three KCNMA1-linked channelopathy mouse models. eLife 2022;11:e77953.
- eLife Digest: ‘The root of the problem‘
Moldenhauer HJ, Dinsdale, RL, Alvarez S, Fernández-Jaén A, and Meredith AL (2022). Effect of an autism-associated KCNMB2 variant, G124R, on BK channel properties. Current Research in Physiology 5: 404-413.
Keros S, Heim J, Hakami W, Zohar-Dayan E, Ben-Zeev B, Grinspan Z, Kruer MC, Meredith AL (2021). Lisdexamfetamine therapy in paroxysmal non-kinesigenic dyskinesia associated with the KCNMA1-N999S variant. Movement Disorders Clinical Practice 9(2): 229–235.
Miller, J, Moldenhauer, HJ, Keros, S, Meredith, AL (2021). An Emerging Spectrum of Variants and Clinical Features in KCNMA1-Linked Channelopathy. Channels 15(1):447‑464.
Buckley C, Williams J, Munteanu T, King M, Park SM, Meredith AL, Lynch T (2020). Dystonicus, Oculogyric Crisis and Paroxysmal Dyskinesia in a 25 Year-Old Woman with a Novel KCNMA1 Variant, K457E. Tremor & Other Hyperkinetic Movements 10(1): 49, pp. 1‑6.
Heim J, Vemuri A, Lewis S, Guida B, Troester M, Keros S, Meredith A, Kruer MC (2020) Cataplexy in patients harboring the KCNMA1 p.N999S mutation. Movement Disorders Clinical Practice 7 (7): 861–862.
Bailey, CS, Moldenhauer, HJ, Park, SM, Keros, S, and Meredith, AL (2019). KCNMA1-Linked Channelopathy. Journal of General Physiology 151 (10): 1173
Moldenhauer, HJ, Park, SM, and Meredith, AL (2020). Characterization of new human KCNMA1 Loss-of-Function Mutations. Biophysical Journal 114A.
Moldenhauer, HJ, Matychak, K, and Meredith, AL (2020). Comparative Gain-of-Function Effects of KCNMA1-N999S Mutation on Human BK Channel Properties. Journal of Neurophysiology 123:560.
- JNP Podcast April 20, 2020
Plante, A, Lai, MH, Lu, J, and Meredith, AL (2019). Effects of single nucleotide polymorphisms in human KCNMA1 on BK current properties. Frontiers in Molecular Neuroscience. 12:285.
Montgomery, JM, and Meredith, AL (2012). Genetic activation of BK currents in vivo generates bi-directional effects on neuronal excitability. PNAS 109(46):18997-9002.
Imlach, WL, Finch, SC, Dunlop, J, Meredith, AL, Aldrich, RW, and Dalziel, JE (2008). The molecular mechanism of ‘ryegrass staggers,’ a neurological disorder of potassium channels. J Pharmacol Exp Ther. 327:657-664.
Circadian Rhythm
Dinsdale R, Roache C, and Meredith AL (2023). Disease-associated KCNMA1 variants decrease circadian clock robustness in channelopathy mouse models. Journal of General Physiology; 155(11):e202313357
McNally BA, Plante AE, and Meredith AL (2021). Contributions of CaV1.3 channels to Ca2+ current and Ca2+-activated BK current in the suprachiasmatic nucleus. Frontiers in Physiology (Special Topic: Regulatory Mechanisms of Ca2+-activated Ion Channels and Their Impacts on Physiological/Pathophysiological Functions).
Plante, AE, Rao, VP, Rizzo, MA, and Meredith, AL (2021). Comparative Ca2+ channel contributions to intracellular Ca2+ levels in the circadian clock. Biophysical Reports 1(1): 100005
Plante, AE, Whitt, JP, and Meredith, AL (2021). BK channel activation by L-type Ca2+ channels CaV1.2 and CaV1.3 during the subthreshold phase of an action potential. J Neurophysiology 126(2):427-439
Harvey, JRM, Plante, A, and Meredith, AL (2020). Ion Channels Controlling Circadian Rhythms in Suprachiasmatic Nucleus Excitability. Physiological Reviews 100(4):1415‑1454
McNally, BA, Plante, AE, and Meredith, AL (2019). Diurnal properties of voltage-gated Ca2+ currents in SCN and roles in action potential firing. Journal of Physiology, 598(9):1775-1790.
Whitt, JP, McNally BA, and Meredith, AL. (2017). Differential contribution of Ca2+ sources to day and night BK current activation in the circadian clock. Journal of General Physiology 150(2):259.
- ‘Up all night: BK channels’ circadian dance with different calcium sources. JGP 150(2):175.
Whitt, JP, Montgomery, JM, and Meredith, AL. (2016). BK channel inactivation gates daytime excitability in the circadian clock. Nature Communications 7:10837.
White, RS, Zemen, BG, Khan, Z, Montgomery, JR, Herrera, GM, and Meredith, AL (2015). Evaluation of mouse urinary bladder smooth muscle for diurnal differences in contractile properties. Frontiers in Pharmacology 5 (293): 1-8.
Shelley, C, Whitt, JP, Montgomery, JM, and Meredith, AL. (2013) Phosphorylation of a constitutive serine inhibits BK channel variants containing the alternate exon ‘SRKR’. Journal of General Physiology 142 (6):585-598.
- Multilevel regulation: Controlling BK channels in central clock neurons
Hermanstyne, T.O., Meredith, A.L., Mong, J.A., Misonou, H (2013). Kv2.2: A novel molecular target to study the role of basal forebrain GABAergic neurons in the sleep-wake cycle. Sleep 36(12):1839-1848.
Montgomery, JM, Whitt, JP, Wright, BN, Lai, ML, and Meredith, AL (2013). Mis-expression of the BK K+ channel disrupts suprachiasmatic nucleus circuit rhythmicity and alters clock-controlled behavior. AJP- Cell Physiology 304(4):C299-C311.
White, RS, Zemen, BG, Khan, Z, Montgomery, JR, Herrera, GM, and Meredith, AL (2015). Evaluation of mouse urinary bladder smooth muscle for diurnal differences in contractile properties. Frontiers in Pharmacology 5 (293): 1-8.
Herrera, GM and Meredith, AL (2010). Diurnal variation in urodynamics of rat. PLoS One 5(8): e12298.
Kent, J and Meredith, AL (2008). BK channels regulate spontaneous action potential rhythmicity in the suprachiasmatic nucleus. PLoS One 3(12):e3884.
Meredith AL, Wiler SW, Miller BH, Takahashi JS, Fodor AA, Ruby NF, and Aldrich RW (2006). BK calcium-activated potassium channels regulate circadian behavioral rhythms and pacemaker output. Nature Neurosci 9(8):1041-1049.
Neurovascular, Cardiovascular and Smooth Muscle Excitability
Lai, MH, Wu, Y, Zhan, Z, Anderson, ME, Dalziel, JE, and Meredith AL (2014). BK channels regulate sinoatrial node firing rate and cardiac pacing in vivo. AJP- Heart 307(9):H1327-38.
Zemen, BG, Lai, MH, Whitt, JP, Khan, Z, Zhao, G, and Meredith, AL (2015). Generation of Kcnma1fl-tdTomato, a conditional deletion of the BK Channel alpha subunit in mouse. Physiological Reports 3(11): e12612.
White, RS, Zemen, BG, Khan, Z, Montgomery, JR, Herrera, GM, and Meredith, AL (2015). Evaluation of mouse urinary bladder smooth muscle for diurnal differences in contractile properties. Frontiers in Pharmacology 5 (293): 1-8.
Girouard H, Bonev AD, Hannah, RM, Meredith AL, Aldrich RW and Nelson MT (2010). Astrocytic endfoot Ca2+ and BK channels determine both arteriolar dilation and constriction. PNAS 107(8):3811-6.
Imlach WL, Finch SC, Miller JH, Meredith AL, Dalziel JE (2010). A role for BK channels in heart rate regulation in rodents. PLoS One 5(1): e8698.
Herrera, GM and Meredith, AL (2010). Diurnal variation in urodynamics of rat. PLoS One 5(8): e12298.
Werner, ME, Zvara, P, Meredith, AL, Aldrich RW, and Nelson, MT (2007). Frequency encoding of cholinergic- and purinergic-mediated signaling to mouse urinary bladder smooth muscle: Modulation by BK channels. Am J Physiol Regul Integr Comp Physiol. 292: R616-624.
Filosa JA, Bonev AD, Straub SV, Meredith AL, Wilkerson MK, Aldrich RW and Nelson MT. (2006). Local potassium signaling couples neuron al activity to vasodilation in the brain. Nature Neurosci. 9(11):1397-1403.
Meredith AL, Thorneloe KS, Werner ME, Nelson MT, and Aldrich RW (2004). Overactive bladder and incontinence in the absence of the BK Ca2+-activated K+ channel. Journal of Biological Chemistry 279:36746-36752.
Additional Neuronal and Neurobehavioral Studies
Zhang, J, Guan , X, Li , Q, Meredith , AL, Pan, HL, & Yan, J (2018). Glutamate-activated K+ signaling complexes formed by BK channels and NMDA receptors. PNAS 115(38):E9006-E9014.
Nelson, A.B., Faulstich, M., Moghadam, S., Onori, K., Meredith, A, and du Lac, S (2017). BK channels are required for multisensory plasticity in the oculomotor system. Neuron 93(1):211-220.
Hayashi, Y, Morinaga, S, Zhang, J, Satoh, Y, Meredith, AL, Nakata, T, Wu, Z, Kohsaka, S, Inoue, K, and Nakanishi, H (2016). BK channels in microglia are required for morphine-induced hyperalgesia. Nature Communications 7: 11697.
Li B, Jie W, Huang L, Wei P, Li S, Luo Z, Friedman AK, Meredith AL, Han MH, Zhu XH, Gao TM (2014). Nuclear BK channels regulate gene expression via the control of nuclear calcium signaling. Nature Neurosci 17(8):1055-63.
Singh, H, Lu, R, Bopassa, JC, Meredith, AL, Stefani, E, and Toro, L (2013). Cardiac mitoBKCa K+ Channel is Encoded by Kcnma1 Gene and a Splicing Sequence Defines its Mitochondrial Location. PNAS 110(26):10836-41.
Wahyu, ID, Kamasawa, N, Matsui, K, Meredith, AL, Watanabe, M, and Shigemoto, R (2013). Quantitative localization of Cav2.1 (P/Q-type) voltage-dependent calcium channels in Purkinje cells: somatodendritic gradient and distinct somatic co-clustering with calcium-activated potassium channels. J Neuroscience 33(8):3668-3678.
Maison, SF, Pyott, SJ, Meredith, AL, and Liberman, MC (2013). Olivocochlear suppression of outer hair cells in vivo: evidence for combined action of BK and SK2 channels throughout the cochlea. J Neurophysiology 109(6):1525-1534.
Pyott SJ, Meredith AL, Fodor AA, Yamoah EN and Aldrich RW. (2007). Normal cochlear function in mice lacking the BK channel α, β1 or β4 subunits. Journal Biological Chemistry 282:3312-3324.
Misonou H, Menegola M, Buchwalder L, Park EW, Meredith A, Rhodes KJ, Aldrich RW, and Trimmer JS. (2006). Localization of the BK Ca2+-activated K+ channel Slo1 in axons and nerve terminals in mammalian brain and cultured neurons. J Comp Neurol. 496:289302.
Book Chapters
Textbook of Ion Channels (Taylor & Francis, 2022)
Genetic Models and Transgenics (Volume 1, Chapter 15)
Alternative Splicing (Volume 3, Chapter 1)