title: Premature changes in neuronal excitability account for hippocampal network impairment and autistic-like behavior in neonatal BTBR T+tf/J mice.
abstract: Coherent network oscillations (GDPs), generated in the immature hippocampus by the synergistic action of GABA and glutamate, both depolarizing and excitatory, play a key role in the construction of neuronal circuits. In particular, GDPs-associated calcium transients act as coincident detectors for enhancing synaptic efficacy at emerging GABAergic and glutamatergic synapses. Here, we show that, immediately after birth, in the CA3 hippocampal region of the BTBR T+tf/J mouse, an animal model of idiopathic autism, GDPs are severely impaired. This effect was associated with an increased GABAergic neurotransmission and a reduced neuronal excitability. In spite its depolarizing action on CA3 pyramidal cells (in single channel experiments EGABA was positive to Em), GABA exerted at the network level an inhibitory effect as demonstrated by isoguvacine-induced reduction of neuronal firing. We implemented a computational model in which experimental findings could be interpreted as the result of two competing effects: a reduction of the intrinsic excitability of CA3 principal cells and a reduction of the shunting activity in GABAergic interneurons projecting to principal cells. It is therefore likely that premature changes in neuronal excitability within selective hippocampal circuits of BTBR mice lead to GDPs dysfunction and behavioral deficits reminiscent of those found in autistic patients.
authors.affiliation: International School for Advanced Studies, via Bonomea 265, 34136 Trieste, Italy.
authors.forename: Giada
authors.initials: G
authors.lastname: Cellot
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University, Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Maggi
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University, Rome, Italy.
authors.forename: Maria Amalia
authors.initials: MA
authors.lastname: Di Castro
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University, Rome, Italy.
authors.forename: Myriam
authors.initials: M
authors.lastname: Catalano
authors.affiliation: Institute of Biophysics, National Research Council, 90146 Palermo, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Migliore
authors.affiliation: Institute of Biophysics, National Research Council, 90146 Palermo, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Migliore
authors.affiliation: Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Scattoni
authors.affiliation: Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Gemma
authors.initials: G
authors.lastname: Calamandrei
authors.affiliation: International School for Advanced Studies, via Bonomea 265, 34136 Trieste, Italy.|European Brain Research Institute, via del Fosso di Fiorano 64, 00143 Rome, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Cherubini
mesh_terms: D000200:Action Potentials; D000818:Animals; D000831:Animals, Newborn; D001321:Autistic Disorder / Q000503:physiopathology*; D001522:Behavior, Animal; D056654:CA3 Region, Hippocampal / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D005680:gamma-Aminobutyric Acid