Memantine protects hippocampal neuronal function in murine human immunodeficiency virus type 1 encephalitis

Abstract

Memantine, a low-to-moderate-affinity NMDA receptor antagonist, can be used to treat cognitive impairment associated with Alzheimer's disease. However, its potential neuroprotective effects for human immunodeficiency virus type 1-associated (HIV-1-associated) dementia are less well appreciated. To this end we studied hippocampal synaptic function in a severe combined immunodeficient (SCID) mouse model of HIV-1 encephalitis (HIVE). Human monocyte-derived macrophages (MDMs) infected with HIV-1(ADA) were injected stereotactically into the caudate and putamen of SCID mice, generating HIVE. These brain subregions are among those most affected in humans. Impaired synaptic transmission and long-term potentiation (LTP) were detected in the CA1 region of hippocampal brain slices of HIVE mice. Memantine-treated HIVE mice showed significant improvements in synaptic function during frequency facilitation tests and LTP induced by high-frequency stimulation when compared with untreated animals. Immunocytochemical measures of neuronal antigens mirrored the neuronal physiological tests. These results demonstrate that memantine attenuates hippocampal synaptic impairment in murine HIVE and provide a rationale for its use in infected humans who experience cognitive decline.

Figure 1.

Evaluation of frequency facilitation in HIVE mice. The comparisons between frequency response recordings were taken at 5.0 Hz (A) and 10.0 Hz (B) in the CA1 region of the mouse hippocampus in SCID mice inoculated with HIV-1-infected MDMs inducing HIVE, MDM, sham, and memantine-treated HIVE mice (HIVE + MEM). C, A 10 pulse paradigm is shown to illustrate the quality of the recorded tracings. D, Bar graphs depict average initial slopes of the 10th pulse in each stimulation and frequency after MDM injection. Statistical comparisons were made with two-tailed Student's t tests. Data points represent mean ± SEM; asterisk denotes significant differences.

Figure 2.

HIVE mice show marked reduction in LTP that is reversed after memantine treatment. A, Comparisons of synaptic potentiation induced in the hippocampi of SCID mice inoculated with HIV-1-infected MDMs inducing HIVE, uninfected MDMs (MDM), media alone (sham), and memantine-treated HIVE mice (HIVE + MEM). Baseline recordings were taken within the first 30 min, followed by a burst stimulus resulting in LTP. Recordings were terminated 60 min after HFS. B, Distinct temporal components, which include PTP, STP, and LTP, are depicted via bar graphs. A significant reduction in PTP, STP, and LTP was observed in the HIVE group. The HIVE group treated with memantine exhibited a higher PTP, STP, and LTP than those components in the control groups. Data points represent mean ± SEM; asterisk denotes significant differences.

Figure 3.

MAP-2 expression within the CA1 region of the hippocampus in HIVE mice treated with memantine. Mice from the four treatment groups (sham, MDM, HIVE, and HIVE + MEM; A-D, respectively) were killed 7 d after injection. All panels represent sections of SCID mouse brains immunostained with antibodies to MAP-2. Hippocampi were identified in coronal sections and then analyzed for MAP-2 immunoreactivity. The same region of the CA1 was selected in all samples. MAP-2 expression was reduced in the MDM and HIVE groups as compared with sham and HIVE + MEM. Primary antibodies were detected by Vectastain Elite kit, using DAB as a substrate, and tissue sections were counterstained with Mayer's hematoxylin, 60×.