title: Altered Functionality, Morphology, and Vesicular Glutamate Transporter Expression of Cortical Motor Neurons from a Presymptomatic Mouse Model of Amyotrophic Lateral Sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a lethal disorder characterized by the gradual degeneration of motor neurons in the cerebrospinal axis. Whether upper motor neuron hyperexcitability, which is a feature of ALS, provokes dysfunction of glutamate metabolism and degeneration of lower motor neurons via an anterograde process is undetermined. To examine whether early changes in upper motor neuron activity occur in association with glutamatergic alterations, we performed whole-cell patch-clamp recordings to analyze excitatory properties of Layer V cortical motor neurons and excitatory postsynaptic currents (EPSCs) in presymptomatic G93A mice modeling familial ALS (fALS). We found that G93A Layer V pyramidal neurons exhibited altered EPSC frequency and rheobase values indicative of their hyperexcitability status. Biocytin loading of these hyperexcitable neurons revealed an expansion of their basal dendrite arborization. Moreover, we detected increased expression levels of the vesicular glutamate transporter 2 in cortical Layer V of G93A mice. Altogether our data show that functional and structural neuronal alterations associate with abnormal glutamatergic activity in motor cortex of presymptomatic G93A mice. These abnormalities, expected to enhance glutamate release and to favor its accumulation in the motor cortex, provide strong support for the view that upper motor neurons are involved early on in the pathogenesis of ALS.
authors.affiliation: I.R.C.C.S. Fondazione S. Lucia, Rome 00143, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Saba
authors.affiliation: I.R.C.C.S. Fondazione S. Lucia, Rome 00143, Italy.
authors.forename: M T
authors.initials: MT
authors.lastname: Viscomi
authors.affiliation: I.R.C.C.S. Fondazione S. Lucia, Rome 00143, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Caioli
authors.affiliation: I.R.C.C.S. Fondazione S. Lucia, Rome 00143, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Pignataro
authors.affiliation: I.R.C.C.S. Fondazione S. Lucia, Rome 00143, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Bisicchia
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata," Rome 00133, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Pieri
authors.affiliation: I.R.C.C.S. Fondazione S. Lucia, Rome 00143, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Molinari
authors.affiliation: I.R.C.C.S. Fondazione S. Lucia, Rome 00143, Italy Institute of Cell Biology and Neurobiology, National Research Council, Rome 00143, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Ammassari-Teule
authors.affiliation: I.R.C.C.S. Fondazione S. Lucia, Rome 00143, Italy Department of Systems Medicine, University of Rome "Tor Vergata," Rome 00133, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Zona
mesh_terms: D000200:Action Potentials; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D000818:Animals; D003712:Dendrites / Q000473:pathology; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009044:Motor Cortex / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology* / Q000502:physiology*; D000072105:Superoxide Dismutase-1 / Q000235:genetics; D013569:Synapses / Q000378:metabolism; D050599:Vesicular Glutamate Transport Protein 2 / Q000378:metabolism*
chemical_list: C000606290:SOD1 protein, human; C493477:Slc17a6 protein, mouse; D050599:Vesicular Glutamate Transport Protein 2; D000072105:Superoxide Dismutase-1; C533711:G9a protein, mouse; D011495:Histone-Lysine N-Methyltransferase
keywords: G93A mice; excitatory neurotransmission; motor neuron hyperexcitability; neuronal morphology; vesicular glutamate transporter