Our goal is to identify, describe, understand, and ameliorate channelopathies associated with cognitive aging, age-related dementias, and other diseases of the brain.
My lab's principal focus is on synapses and dendrites of neurons from animals and humans over the course of chronological aging or those afflicted with age-related dementia (e.g., Alzheimer's disease) or neurological disease (e.g., intractable epilepsy). Our approach combines immunogold serial section electron microscopy, array tomography, 2-photon calcium imaging, and patch-clamp physiology. We are currently focusing on the degradation of hippocampal synapses and dendrites in aged, cognitively impaired rats and transgenic mice harboring Alzheimer's disease-related mutations, as well as aged humans lucky enough to escape the ravages of cognitive aging and those with Alzheimer's disease. Our techniques allow us to identify patterns of synaptic or dendritic degradation with electron microscopy and array tomography, and then determine the functional consequences of this disassembly on synaptic transmission, neuronal function, calcium signaling, and plasticity using 2-photon imaging and patch-clamp recordings. Our hope is that we can help provide a map of the neurobiological proteomic constellations that demarcate successful and unsuccessful cognitive agers, as well as identify chemicals that correct neuronal signaling at the functional and molecular levels.
Simkin D, Hattori S, Ybarra N, Musial TF, Buss EW, Richter H, Oh MM, Nicholson DA, Disterhoft JF (2015) Aging-related hyperexcitability in CA3 pyramidal neurons is mediated by enhanced A-type K+ channel function and expression. Journal of Neuroscience 35:13206-13218.
Neuman KM, Molina-Campos E, Musial TF, Price AL, Oh KJ, Wolke ML, Buss EW, Scheff SW, Mufson EJ, Nicholson DA (2015) Evidence for Alzheimer's disease-linked synapse loss and compensation in mouse and human hippocampal CA1 pyramidal neurons. Brain Structure and Function 220:3143-3165.
Menon V, Musial TF, Liu A, Katz Y, Kath WL, Spruston N, Nicholson DA (2013) Balanced synaptic impact via distance-dependent synapse distribution and complementary expression of AMPARs and NMDARs in hippocampal dendrites. Neuron 80:1451-1463.
Kandalepas PC, Sadleir KR, Eimer WA, Zhao J, Nicholson DA, Vassar R (2013) The Alzheimer's beta-secretase BACE1 localizes to normal presynaptic terminals and to dystrophic presynaptic terminals surrounding amyloid plaques. Acta Neuropathologica 26:329-352.
Dougherty KA, Nicholson DA, Diaz L, Buss EW, Neuman KM, Chetkovich DM, Johnston D (2013) Differential expression of HCN subunits alters voltage-dependent gating of h-channels in CA1 pyramidal neurons from dorsal and ventral hippocampus. Journal of Neurophysiology 109:1940-1953.
Katz Y, Menon V, Nicholson DA, Geinisman Y, Kath WL, Spruston N (2009) Synapse distribution suggests a two-stage model of dendritic integration in CA1 pyramidal neurons. Neuron 63:171-177.
Nicholson DA, Geinisman Y (2009) Axospinous synaptic subtype-specific differences in structure, size, ionotropic receptor expression, and connectivity in apical dendritic regions of rat hippocampal CA1 pyramidal neurons. Journal of Comparative Neurology 512:399-418.
Nicholson DA, Trana R, Katz Y, Kath WL, Spruston N, Geinisman Y (2006) Distance-dependent differences in synapse number and AMPA receptor expression in hippocampal CA1 pyramidal neurons. Neuron 50:431-442.
Nicholson DA, Yoshida R, Berry RW, Gallagher M, Geinisman Y (2004) Reduction in size of perforated postsynaptic densities in hippocampal axospinous synapses and age-related spatial learning impairments. Journal of Neuroscience 25:7648-7653.