Abstract
One of the aspects of Alzheimer disease is loss of cholinergic neurons in the basal forebrain, which leads to development of cognitive impairment. Here, we used a model of cholinergic deficit caused by immunotoxin 192IgG-saporin to study possible beneficial effects of adeno-associated virus (AAV)–mediated overexpression of nerve growth factor (NGF) in the hippocampus of rats with cholinergic deficit. Suspension of recombinant AAV carrying control cassette or cassette with NGF was injected into both hippocampi of control rats or rats with cholinergic deficit induced by intraseptal injection of 192IgG-saporin. Analysis of choline acetyltransferase (ChAT) immunostaining showed that NGF overexpression in the hippocampus did not prevent strong loss of ChAT-positive neurons in the septal area caused by the immunotoxin. Induction of cholinergic deficit in the hippocampus led to impairments in Y-maze and beam-walking test but did not affect behavioral indices in the T-maze, open field test, and inhibitory avoidance training. NGF overexpression in the rats with cholinergic deficit restored normal animal behavior in Y-maze and beam-walking test. Recording of field excitatory postsynaptic potentials in vivo in the hippocampal CA1 area showed that induction of cholinergic deficit decreased magnitude of long-term potentiation (LTP) and prevented a decrease in paired-pulse ratio after LTP induction, and NGF overexpression reversed these negative changes in hippocampal synaptic characteristics. The beneficial effect of NGF was not associated with compensatory changes in the number of cells that express NGF receptors TrkA and NGFR in the hippocampus and medial septal area. NGF overexpression also did not prevent a 192IgG-saporin–induced decrease in the activity of acetylcholine esterase in the hippocampus. We conclude that NGF overexpression in the hippocampus under conditions of cholinergic deficit induces beneficial effects which are not related to maintenance of cholinergic function.
Highlights
The basal forebrain cholinergic neurons in the medial septal area, diagonal band of Broca (MS/DBB), and nucleus basalis innervate various structures of the brain
Animals belonged to one of three groups: 192IgG-saporin– injected rats with control virus expressing green fluorescent protein (GFP) (SAP-GFP; n = 10 for electrophysiological experiments, n = 9 for behavioral experiments), phosphatebuffered saline (PBS) injected control rats treated with control virus construction (PBS-GFP; n = 8 for electrophysiology, n = 10 for behavior), and 192IgG-saporin–injected rats treated with adeno-associated virus (AAV) carrying cassette with nerve growth factor (NGF) and GFP separated by internal ribosome entry site (IRES) (NGF-IRES-GFP) (SAP-NGF; n = 9 for electrophysiological experiments, n = 10 for behavioral experiments)
In order to estimate a possible effect of 192IgG-saporin and a possible protective effect of NGF after the simultaneous administration of the toxin and Ngf -containing or control vectors into the medial septum or hippocampus, respectively, FIGURE 1 | Immunostaining of hippocampal slices with antibody against GFP and DAPI staining in the hippocampus control rats (A) and rats with cholinergic deficit (B,C), which were transduced with AAV carrying either GFP alone (A,B) or NGF-IRES-GFP (C)
Summary
The basal forebrain cholinergic neurons in the medial septal area, diagonal band of Broca (MS/DBB), and nucleus basalis innervate various structures of the brain. Their major functions include modulation of synaptic plasticity and excitability of cortical and hippocampal neurons. The link between pathological manifestations and degeneration of cholinergic neurons is supported by findings made in animal studies where disruption of cholinergic signaling leads to impaired synaptic plasticity (Hirotsu et al, 1989; Sokolov and Kleschevnikov, 1995; Motooka et al, 2001; Dobryakova et al, 2020a), altered network functioning (Dannenberg et al, 2017), and cognitive deficits (Blokland, 1995). Cholinergic agonists can enhance cognition (Drachman and Leavitt, 1974), and potentiation of cholinergic function by acetylcholinesterase inhibitors improves cognitive state of patients with Parkinson disease (Emre et al, 2004; Pagano et al, 2015)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
