[Frontiers in Bioscience 7, d593-607, March 1, 2002]

BORNA DISEASE VIRUS INFECTION OF THE NEONATAL RAT: DEVELOPMENTAL BRAIN INJURY MODEL OF AUTISM SPECTRUM DISORDERS

Mikhail V. Pletnikov1,2, Timothy H. Moran1, and Kathryn M. Carbone1,2,3

Departments of 1Psychiatry and Behavioral Sciences and 3Medicine, The Johns Hopkins University School of Medicine, Ross 618, 720 Rutland Avenue, Baltimore, MD 21205; 2Laboratory of Pediatric and Respiratory Viral Diseases, CBER, FDA, Bldg. 29A, Rm. 1A-21, HFM-460, 8800 Rockville Pike, Bethesda, 20892 MD, USA

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Animal models of psychiatric disorders
4. Neonatal Borna disease virus infection as a new model of autism
4.1. Borna disease virus
4.2. Neonatal BDV infection
5. Autistic-like features of neonatal BDV infection
5.1. Appearance, physical growth
5.2. Neuropathology
5.2.1. The distribution of the virus
5.2.2. Neonatal BDV infection-induced autistic-like developmental brain injury
5.2.2.1. Cerebellum
5.2.2.2. Hippocampus
5.2.2.3. Neocortex
5.2.2.4. Other brain regions involved
5.2.2.5. The molecular mechanisms of neuronal loss
5.3. BDV-induced immune alterations
5.3.1. BDV-associated activation of astroglia and microglia
5.3.2. BDV-induced activation of cytokines and chemokines
5.4. Behavioral deficits
5.4.1. Sensorimotor behaviors
5.4.2. Emotion and anxiety
5.4.3. Cognitive behavior
5.4.3.1. Spatial discrimination learning
5.4.3.2. Spatial learning and memory
5.4.3.3. Fear conditioning
5.4.3.4. Aversive leaning
5.4.4. Social behavior
5.5. Neurochemical alterations
6. Perspectives
7. Acknowledgement
8. References

Autism spectrum disorders (ASD) have been the focus of a great deal of research and clinical speculation. This intense interest relates to both the perplexing pathogenesis and devastating consequences of these disorders. One of the obstacles to understanding the pathogenesis of autism and its efficient treatment has been the paucity of animal models that could be used for hypotheses-driven mechanistic studies of abnormal brain and behavior development and for the pre-clinical testing novel pharmacological treatments. The present review provides a detailed analysis of a new animal model of ASD. This model utilizes neonatal Borna disease virus (BDV) infection of the rat brain as a unique experimental teratogen to study the pathogenesis of neurodevelopmental damage.

For more than a decade, studies of the BDV animal model have yielded much insight into the pathogenic processes of abnormal brain development and resulting autistic-like behavioral abnormalities in rats. The most recent experiments demonstrate the utility of the BDV model for studying the pathophysiological mechanisms of the gene-environment interaction that determines differential disease outcomes and variability in responses to treatments.