Nerve growth factor in the hippocamposeptal system: evidence for activity-dependent anterograde delivery and modulation of synaptic activity.
Neurotrophins have been implicated in regulating neuronal differentiation, promoting neuronal survival, and modulating synaptic efficacy and plasticity. The prevailing view is that, depending on the target and mode of action, most neurotrophins can be trafficked and released either anterogradely or retrogradely in an activity-dependent manner. However, the prototypic neurotrophin, nerve growth factor (NGF), is not thought to be anterogradely delivered. Here we provide the neuroanatomical substrate for an anterograde hippocamposeptal transport of NGF by demonstrating its presence in mouse hippocampal GABAergic neurons and in their hippocamposeptal axons that ramify densely and abut neurons in the medial septum/diagonal band of Broca (MS/DB). We also demonstrate an activity-dependent increase in septal NGF levels that is dependent on the pattern of intrahippocampal stimulation. In addition, we show that acute exposure to NGF, via activation of TrkA, attenuates GABA(A) receptor-mediated inhibitory synaptic currents and reduces sensitivity to exogenously applied GABA. These acute actions of NGF display cell type and functional selectivity insofar as (1) they were found in cholinergic, but not GABAergic, MS/DB neurons, and (2) glutamate-mediated excitatory synaptic activity as well as AMPA-activated current responses were unaffected. Our results advocate a novel anterograde, TrkA-mediated NGF signaling in the CNS.
Department of Physiology and Neurobiology, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA.
Lan
L
Guo
Mason L
ML
Yeh
Verginia C
VC
Cuzon Carlson
Erin M
EM
Johnson-Venkatesh
Hermes H
HH
Yeh
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001703:Biophysics; D002795:Choline O-Acetyltransferase / Q000235:genetics; D004558:Electric Stimulation; D004797:Enzyme-Linked Immunosorbent Assay; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D007839:Functional Laterality; D018682:GABA Agents / Q000494:pharmacology; D059330:GABAergic Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D005968:Glutamate Decarboxylase / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology* / Q000378:metabolism*; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D020932:Nerve Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects; D009434:Neural Pathways / Q000502:physiology; D018408:Patch-Clamp Techniques; D012686:Septal Nuclei / Q000166:cytology; D020665:Septum of Brain / Q000166:cytology; D013569:Synapses / Q000502:physiology*
D018683:Excitatory Amino Acid Agents; D018682:GABA Agents; D049452:Green Fluorescent Proteins; D020932:Nerve Growth Factor; D002795:Choline O-Acetyltransferase; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1