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Altered brain fyn kinase in a murine acquired immunodeficiency syndrome
Y Sei1, L Whitesell, Y Kustova
1Laboratory of Neuroscience, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Abstract:
Mice infected with the replication-defective virus (BM5def) in the LP-BM5 murine leukemia virus (MuLV) mixture develop an immune deficiency syndrome and encephalopathy characterized by impaired spatial learning and memory as demonstrated in the Morris water maze. However, the molecular mechanism (or mechanisms) underlying this cognitive deficit remains unknown. Here we report that brain fyn kinase, which has been proposed to be involved in spatial learning and memory, was unresponsive to glutamatergic stimulation in mice with MAIDS. Thus, whereas application of glutamate to hippocampal slices from control mice increased fyn protein tyrosine kinase (PTK) activity more than 2.5-fold, these changes were significantly impaired in LP-BM5 MuLV-infected mice. Moreover, mice with MAIDS exhibited an abnormal histological distribution of fyn PTK in the hippocampus. These findings suggest that virus-associated disruption of fyn kinase-mediated signaling contributes to the cognitive deficits observed in mice with MAIDS and other retrovirus-induced encephalopathies.
Insights
Mice with immune deficiency show impaired spatial learning due to altered fyn kinase activity in the brain. This study reveals a molecular link between retroviral infection and cognitive deficits.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Murine acquired immune deficiency syndrome (MAIDS) impairs cognitive functions, including spatial learning and memory.
- The molecular mechanisms underlying MAIDS-associated encephalopathy and cognitive deficits are not fully understood.
- Fyn kinase, a protein tyrosine kinase, is implicated in learning and memory processes.
Purpose of the Study:
- To investigate the role of fyn kinase in the cognitive deficits observed in mice with MAIDS.
- To determine if glutamatergic stimulation affects fyn kinase activity in the hippocampus of MAIDS mice.
- To explore the impact of LP-BM5 MuLV infection on fyn kinase signaling pathways.
Main Methods:
- Utilized the LP-BM5 murine leukemia virus (MuLV) model to induce MAIDS in mice.
- Assessed spatial learning and memory using the Morris water maze.
- Measured fyn protein tyrosine kinase (PTK) activity in hippocampal slices following glutamate stimulation.
- Examined the histological distribution of fyn PTK in the hippocampus of control and infected mice.
Main Results:
- Mice with MAIDS exhibited significant impairments in spatial learning and memory.
- Glutamatergic stimulation failed to increase fyn PTK activity in hippocampal slices from MAIDS mice, unlike in control mice.
- Abnormal histological distribution of fyn PTK was observed in the hippocampus of MAIDS mice.
- These findings indicate a disruption in fyn kinase-mediated signaling in the brains of MAIDS mice.
Conclusions:
- Virus-associated disruption of fyn kinase signaling contributes to cognitive deficits in MAIDS.
- Impaired fyn kinase responsiveness to glutamatergic stimulation is a key factor in MAIDS-related encephalopathy.
- This study provides insights into the molecular basis of retrovirus-induced cognitive impairments.