Persistent dentate granule cell hyperexcitability after neonatal infection with lymphocytic choriomeningitis virus

Abstract

Infection of neonatal Lewis rats with lymphocytic choriomeningitis virus (LCMV) produces distinct retinal, cerebellar, and hippocampal neuropathology. To understand the neurophysiological consequences of LCMV-induced hippocampal pathology, we studied evoked monosynaptic potentials and electro-encephalographic (EEG) activity in the dentate gyrus and CA1 and CA3 subfields of the hippocampus in vivo. Lewis rats were inoculated intracerebrally with LCMV at postnatal day 4. In rats studied 84-107 d postinfection, virus was cleared from the dentate gyrus and the number of dentate granule cells was decreased by 70%. No viral antigen or cell loss was apparent in CA1 or CA3. The hippocampal EEG of LCMV-infected rats 84-102 d postinfection was dominated by continuous theta. Although evoked potentials elicited in CA1 and CA3 by monosynaptic afferent stimulation revealed no differences between sham- and LCMV-infected rats, there was a site-specific dissociation of synaptic [population excitatory postsynaptic potential (pEPSP)] and cellular (population spike) responses and a suppression of GABA-mediated recurrent inhibition in the dentate gyrus of LCMV-infected rats. These findings indicate that GABA-mediated inhibition was markedly decreased in LCMV-infected rats. In support of this, parvalbumin-immunoreactive cell bodies and neuronal processes were decreased in LCMV-infected rats, suggesting that a subpopulation of GABA interneurons was affected. These findings indicate that abnormalities in synaptic function persist after clearance of infectious virus from the central nervous system and suggest that decreased inhibition subsequent to pathological sequence in a subpopulation of GABA interneurons may be implicated in the hyperexcitability of dentate granule cells.

Viral-like brain inflammation during development causes increased seizure susceptibility in adult rats

“…In addition, post-mortem sections from the temporal lobes of patients who suffered seizures as a result of HSV infection show robust pro-inflammatory infiltrates relative to other brain regions (Chadwick, 2005;Esiri, 1982;Jay et al, 1998;Theodore et al, 2008;Yamada et al, 2003). These findings have led some to suspect that the epileptogenicity of viral encephalitis results from the recruitment of the hippocampus causing long-term excitability (Chen et al, 2004;Wu et al, 2003), even in the absence of acute or chronic cytological injury (Beers et al, 1993;Rempel et al, 2005); while others have proposed that marked neuronal damage contributes to the hyperexcitable state (Pearce et al, 1996).…”

Schizophrenia and viral infection during neurodevelopment: a focus on mechanisms

“…90,91 Moreover, reduced hippocampal volume and lateral ventricular enlargement are among the most consistent neuroanatomical findings in the disease. 7,89 To model abnormalities of hippocampal development, rats are infected intracranially with LCMV at 4 days old as originally described by Monjan et al 167,[172][173][174] At this age, the developmental stage of the rat hippocampal dentate gyrus corresponds to the stage of the human dentate gyrus attained during the second trimester in utero; 171,175 this is commonly thought to be the critical period for a neurodevelopmental insult to trigger schizophrenia. 8,33 In these rats, LCMV shows stark specificity for which neurons it infects, including neuronal subsets in the hippocampus.…”

“…8,33 In these rats, LCMV shows stark specificity for which neurons it infects, including neuronal subsets in the hippocampus. [172][173][174]176 By examining the consequences of this cell-type selective infection we endeavor to uncover clues to the genesis of hippocampal circuitry abnormalities in schizophrenia.…”

“…172 Accordingly, immunohistochemistry has revealed a decrease in a subset of GABAergic cells (those expressing parvalbumin). 172 As the rats proceed toward sexual maturity, degeneration of dentate granule cells becomes apparent, 167,172,179 and the adults manifest varying degrees of hippocampal volume reduction and lateral ventricular dilation.…”

Distinct neural stem cell tropism, early immune activation, and choroid plexus pathology following coxsackievirus infection in the neonatal central nervous system

“…25,26 The surviving host may exhibit permanent abnormalities in synaptic function, a decrease in GABA-mediated inhibition, and hippocampal neuropathology following LCMV infection. 27 Therefore, we wished to inspect progenitor cell tropism of both viruses in greater detail by immunofluorescence microscopy utilizing wellcharacterized cell markers for neural (nestin þ ) and glial (olig2 þ ) progenitor cells.…”