Transgenic mice with cerebral expression of human immunodeficiency virus type-1 coat protein gp120 show divergent changes in short- and long-term potentiation in CA1 hippocampus.
The human immunodeficiency virus type-1 envelope glycoprotein gp120 is shed from the virus and from infected cells and thus can diffuse and interact with a variety of central nervous system cells. Transgenic mice constitutively expressing glial fibrillary acidic protein-driven gp120 from brain astrocytes display neuronal and glial changes resembling abnormalities in human immunodeficiency virus type-1-infected human brains. To assess the neurophysiology of these transgenic mice and determine whether gp120 expression impairs synaptic plasticity, we examined CA1 population excitatory postsynaptic potentials in hippocampal slices from transgenic mice and from non-transgenic controls, using a double-blind protocol. Compared with slices from non-transgenic littermate controls, slices from gp120 transgenic mice showed four significant alterations: (i) increased mean slopes of normalized population excitatory postsynaptic potentials; (ii) larger paired-pulse facilitation after induction of long-term potentiation at 50 ms interpulse intervals; (iii) markedly elevated short-term potentiation after 10 and 20 shocks at 100 Hz; and (iv) a significant reduction in the magnitude of CA1 long-term potentiation. In slices from transgenic mice expressing Escherichia coli beta-galactosidase from the same promoter, paired-pulse facilitation and long-term potentiation were normal. These results indicate that brain slice preparations from gp120 transgenic mice can be used to assess pathophysiological effects of gp120 on neuronal networks. Because short-term potentiation involves presynaptic mechanisms, our results suggest that gp120 expression in these mice enhances either presynaptic glutamate release or postsynaptic glutamate receptor function, or both. These changes could lead to increased Ca2+ influx, thereby contributing to neuronal dysfunction and injury. As long-term potentiation is a cellular model of learning and memory, our results may be relevant to memory (cognitive) impairments seen in patients with AIDS.
Krucker
T
T
Scripps Research Institute and AIDS Research Center, Department of Neuropharmacology, La Jolla, CA 92037, USA.
Toggas
S M
SM
Mucke
L
L
Siggins
G R
GR
D000818:Animals; D001921:Brain / Q000378:metabolism*; D004558:Electric Stimulation / Q000379:methods; D005260:Female; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000502:physiology*; D007763:Lac Operon / Q000235:genetics; D017774:Long-Term Potentiation / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics / Q000378:metabolism*
D015699:HIV Envelope Protein gp120