In the adult hippocampus, chronic nerve growth factor deprivation shifts GABAergic signaling from the hyperpolarizing to the depolarizing direction.
GABA, the main inhibitory transmitter in adulthood, early in postnatal development exerts a depolarizing and excitatory action. This effect, which results from a high intracellular chloride concentration ([Cl(-)](i)), promotes neuronal growth and synaptogenesis. During the second postnatal week, the developmental regulated expression of the cation-chloride cotransporter KCC2 accounts for the shift of GABA from the depolarizing to the hyperpolarizing direction. Changes in chloride homeostasis associated with high [Cl(-)](i) have been found in several neurological disorders, including temporal lobe epilepsy. Here, we report that, in adult transgenic mice engineered to express recombinant neutralizing anti-nerve growth factor antibodies (AD11 mice), GABA became depolarizing and excitatory. AD11 mice exhibit a severe deficit of the cholinergic function associated with an age-dependent progressive neurodegenerative pathology resembling that observed in Alzheimer patients. Thus, in hippocampal slices obtained from 6-month-old AD11 (but not wild-type) mice, the GABA(A) agonist isoguvacine significantly increased the firing of CA1 principal cells and, at the network level, the frequency of multiunit activity recorded with extracellular electrodes. In addition, in AD11 mice, the reversal of GABA(A)-mediated postsynaptic currents and of GABA-evoked single-channel currents were positive with respect to the resting membrane potential as estimated in perforated patch and cell attached recordings, respectively. Real-time quantitative reverse transcription-PCR and immunocytochemical experiments revealed a reduced expression of mRNA encoding for Kcc2 and of the respective protein. This novel mechanism may represent a homeostatic response that counterbalances within the hippocampal network the Alzheimer-like neurodegenerative pathology found in AD11 mice.
Lagostena
Laura
L
Neuroscience Programme, International School for Advanced Studies, 34014 Trieste, Italy.
Rosato-Siri
Marcelo
M
D'Onofrio
Mara
M
Brandi
Rossella
R
Arisi
Ivan
I
Capsoni
Simona
S
Franzot
Jessica
J
Cattaneo
Antonino
A
Cherubini
Enrico
E
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D057134:Antibodies, Neutralizing / Q000235:genetics; D001703:Biophysics; D002034:Bumetanide / Q000494:pharmacology; D004558:Electric Stimulation / Q000379:methods; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000166:cytology* / Q000502:physiology; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects / Q000235:genetics; D007539:Isonicotinic Acids / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D020932:Nerve Growth Factor / Q000037:antagonists & inhibitors* / Q000276:immunology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011724:Pyridazines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology; D027981:Symporters / Q000378:metabolism; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism* / Q000494:pharmacology; D000096922:K Cl- Cotransporters
D015763:2-Amino-5-phosphonovalerate; D057134:Antibodies, Neutralizing; D002034:Bumetanide; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018755:GABA Agonists; D018756:GABA Antagonists; D007539:Isonicotinic Acids; D020932:Nerve Growth Factor; D011724:Pyridazines; D011810:Quinoxalines; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D049994:Sodium Potassium Chloride Symporter Inhibitors; D027981:Symporters; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D005680:gamma-Aminobutyric Acid; D000096922:K Cl- Cotransporters; C056723:FG 9041; C049853:gabazine; C015300:isoguvacine