Abnormalities in brain development has been implicated in several neuropsychiatric disorders including schizophrenia, autism, and temporal lobe epilepsy. Brain imaging studies and neuropathological observations suggest that at least some of these abnormalities occur in the hippocampal formation. While the etiology of these disorders remains elusive, recent studies have suggested the involvement of a perinatal insult such as a viral infection. However, the information which can be gained from human postmortem studies may be limited because a viral infection could insidiously disrupt development and then be cleared from the brain prior to the manifestation of symptoms. Furthermore, because the immune system would likely be immature at the time of infection, the detection of the immunological hallmarks of infection could be problematic. Thus animal studies are needed to investigate the mechanisms by which a transient viral infection affecting the hippocampus during development can lead to neuropathological and functional changes in the adult. The goals of this proposal are to explore the mechanisms by which infection of rats with lymphocytic choriomeningitis virus (LCMV) during development can initiate a neuropathological cascade in the hippocampus resulting in the continued loss of dentate granule cells in the absence of detectable virus. Electrophysiological data in adult rats which have cleared the virus indicate a loss of GABAergic inhibition in the hippocampal dentate gyrus. Preliminary data suggest this disinhibition is due to an early infection and loss of inhibitory interneurons. Thus, disruption of inhibitory circuits during neurodevelopment could lead to excessive glutamatergic input on dentate granule cells, which would then die gradually due to excitotoxic. Alternatively LCMV could be acting through IL-1b and BDNF to retard the maturation of inhibitory circuits during postnatal development, leading to the latent excitotoxic loss of dentate granule cells. Therefore, Aim 1 will test the hypothesis the LCMV infection causes an early derangement of inhibitory circuits and a consequential unleashing of excitotoxic synapses on hippocampal dentate granule cells. Specifically, 4 day old rats will be infected intracranially with LCMV and the infection and loss of hippocampal neurons involved in inhibitory circuits will be measured as the disease progresses between 6 and 180 days post infection.
Aim 2 will determine if blocking excitatory amino acids or facilitating inhibitory neurotransmission will ameliorate LCMV-mediated dentate granule cell loss at 90 and 180 days post infection.
Aim 3 will determine if LCMV-induced production of IL-1b can decrease BDNF in the developing hippocampus, and thus interrupt the differentiation of BDNF-dependent interneurons. These studies aim to provide clues to the mechanisms by which an early viral infection could be involved in certain neurodevelopmental disorders.
|Pearce, B D (2001) Schizophrenia and viral infection during neurodevelopment: a focus on mechanisms. Mol Psychiatry 6:634-46|
|Pearce, B D; Valadi, N M; Po, C L et al. (2000) Viral infection of developing GABAergic neurons in a model of hippocampal disinhibition. Neuroreport 11:2433-8|
|Pearce, B D; Po, C L; Pisell, T L et al. (1999) Lymphocytic responses and the gradual hippocampal neuron loss following infection with lymphocytic choriomeningitis virus (LCMV). J Neuroimmunol 101:137-47|