Involvement of CDC25Mm/Ras-GRF1-dependent signaling in the control of neuronal excitability.
Ras-GRF1 is a neuron-specific guanine nucleotide exchange factor for Ras proteins. Mice lacking Ras-GRF1 (-/-) are severely impaired in amygdala-dependent long-term synaptic plasticity and show higher basal synaptic activity at both amygdala and hippocampal synapses (Brambilla et al., 1997). In the present study we investigated the effects of Ras-GRF1 deletion on hippocampal neuronal excitability. Electrophysiological analysis of both primary cultured neurons and adult hippocampal slices indicated that Ras-GRF1-/- mice displayed neuronal hyperexcitability. Ras-GRF1-/- hippocampal neurons showed increased spontaneous activity and depolarized resting membrane potential, together with a higher firing rate in response to injected current. Changes in the intrinsic excitability of Ras-GRF1-/- neurons can entail these phenomena, suggesting that Ras-GRF1 deficiency might alter the balance between ionic conductances. In addition, we showed that mice lacking Ras-GRF1 displayed a higher seizure susceptibility following acute administration of convulsant drugs. Taken together, these results demonstrated a role for Ras-GRF1 in neuronal excitability.
Tonini
R
R
Dipartimento di Fisiologia e Biochimica Generali, Università degli Studi di Milano, 20133 Milan, Italy.
Franceschetti
S
S
Parolaro
D
D
Sala
M
M
Mancinelli
E
E
Tininini
S
S
Brusetti
R
R
Sancini
G
G
Brambilla
R
R
Martegani
E
E
Sturani
E
E
Zippel
R
R
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D004558:Electric Stimulation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009415:Nerve Net / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D016708:Synaptophysin / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology; D020666:ras-GRF1 / Q000172:deficiency* / Q000235:genetics
D018691:Excitatory Amino Acid Antagonists; D007527:Isoenzymes; D016708:Synaptophysin; D020666:ras-GRF1; D013779:Tetrodotoxin; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1