The major research interest of this lab is constructing developmental animal
models that reproduce various aspects of schizophrenia, and help understand
mechanisms underlying schizophrenia and mode of action of antipsychotic drugs.
The hippocampal lesion model, developed in our laboratory has been awarded in
1996 the U.S. Patent for screening and developing novel antipsychotic treatments.
In a series of studies described in over 20 published papers, we have demonstrated
that some behavioral abnormalities associated with the neonatal hippocampal lesion
in the rat remain relatively quiet until a certain time in development while others
appear early after the lesion, and that the profile of changes depends upon the age
at which damage is induced. We have also shown that chronic treatment with
antipsychotic drugs suppresses some of the behavioral abnormalities.
The behavioural deficits observed in the neonatally treated rats closely resemble
the clinical pattern, both with respect to phenomenology (some aspects of the negative
and positive symptoms of schizophrenia are mimicked in the lesioned rat) and to the
temporal pattern of symptom onset (abnormalities corresponding to the negative symptoms
are present early in life, while those corresponding to the positive symptoms emerge
in early adulthood). In a study on different genetic strains of rats, we have extended
the model to include genetically determined factors that may explain additional clinical
phenomena associated with schizophrenia, in particular variations across individuals in
apparent genetic loading, in severity of symptoms, and in age of onset.
The future projects will include exploring the intracellular molecular events
following the hippocampal damage in order to elucidate mechanisms underlying behavioral
deficits and differential efficacy of typical versus atypical neuroleptic drugs. We are
currently in the process of screening the expression of immediate early genes and other
genes implicated in neuroleptic drug action using both in situ hybridization and RNase
protection assays in the lesion model.
1. Lipska BK, Lerman D, Khaing ZZ, Weickert CS, Weinberger DR. Gene expression in dopamine and GABA systems in an animal model of schizophrenia: Effects of antipsychotic drugs. Eur J Neurosci, in press, 2003.
2. Nadri C, Lipska BK, Kozlovsky N, Weinberger DR, Belmaker RH, Agam G. GSK-3 levels and activity in a neurodevelopmental rat model of schizophrenia. Brain Res Dev Brain Res, 141, 33-37, 2003.
3. Chrapusta SJ, Egan MF, Wyatt RJ, Weinberger DR, Lipska BK. Neonatal ventral hippocampal damage modifies serum corticosterone and dopamine release responses to acute footshock in adult rats. Synapse 47:270-277, 2003.
4. Weickert CS, Hyde TM, Lipska BK, Herman MM, Weinberger DR, Kleinman JE. Reduced brain derived neurotrophic factor in prefrontal cortex of patients with schizophrenia. Mol Psychiatry. In press, 2003.
5. Matsumoto M, Shannon Weickert C, Akil M, Lipska BK, Hyde TM, Herman MM, Kleinman JE, Weinberger DR. Catechol O-methyltransferase (COMT) mRNA expression in human and rat brain: evidence for a role in cortical neuronal function. Neuroscience, 2003;116(1):127-37.
6. Halim ND, Weickert SC, McClintock BW, Hyde TM, Weinberger DR, Kleinman JE, Lipska BK. Presynaptic proteins in the prefrontal cortex of patients with schizophrenia and in rats with abnormal prefrontal development. Mol Psychiatry. In press, 2003.
7. Eells JB, Lipska BK, Yeung SK, Misler JA, Nikodem VM. Nurr1-null heterozygous mice have reduced mesolimbic and mesocortical dopamine levels and increased stress-induced locomotor activity. Behav Brain Res 136, 267-275, 2002.
8. Lipska BK, Luu S, Halim ND, Weinberger DR. Behavioral effects of neonatal and adult excitotoxic lesions of the mediodorsal thalamus in the adult rat. Behav Brain Res. In press, 2003.
9. Lipska BK, Halim ND, Segal PN, Weinberger DR. Effects of reversible inactivation of the neonatal ventral hippocampus on behavior in the adult rat. J Neurosci 22, 2835-2842, 2002.
10. Lipska BK, Aultman JM, Verma A, Weinberger DR, Moghaddam B. Neonatal damage of the ventral hippocampus impairs working memory in the rat. Neuropsychopharmacology 27, 47-54, 2002.
11. Bertolino A, Roffman JL, Lipska BK, van Gelderen P, Olson A, Weinberger DR. Reduced N-acetyl-aspartate in prefrontal cortex of adult rats with neonatal hippocampal damage. Cerebral Cortex 12, 983-990, 2002.
12. O'Donnell P, Lewis BL, Weinberger DR, Lipska BK. Neonatal hippocampal damage alters electrophysiological properties of prefrontal cortical neurons. Cerebral Cortex, 12, 975-982, 2002.
13. Weinberger DR, Egan MF, Bertolino A, Callicott JH, Mattay VS, Lipska BK, Berman KF, Goldberg TE. Prefrontal neurons and the genetics of schizophrenia. Biol Psychiatry 50, 825-844, 2001.
14. Lipska BK, Khaing ZZ, Shannon Weickert C, Weinberger DR. BDNF mRNA expression in rat hippocampus and prefrontal cortex: effects of neonatal ventral hippocampal damage and antipsychotic drugs. Eur J Neurosci, 14, 135-144, 2001.
15. Molteni R, Lipska BK, Weinberger DR, Racagni G, Riva MA. Developmental and stress-related changes of neurotrophic factor gene expression in an animal model of schizophrenia. Mol Psychiatry 6, 285-292, 2001.
16. Al-Amin HA, Weickert CS, Lillrank SM, Weinberger DR, Lipska BK. Delayed onset of enhanced MK-801-induced motor hyperactivity after neonatal lesions of the rat ventral hippocampus. Biol Psychiatry 49, 528-539, 2001.
17. Roffman JL, Lipska BK, Bertolino A, Van Gelderen P, Olson AW, Khaing ZZ, Weinberger DR. Local and downstream effects of excitotoxic lesions in the rat medial prefrontal cortex on in vivo 1H-MRS signals. Neuropsychopharmacology 22, 430-439, 2000.
18. Lipska BK, Weinberger DR. To model a psychiatric disorder in animals: Schizophrenia as a reality test. Neuropsychopharmacology 23, 223-239, 2000.
19. Al-Amin HA, Weinberger DR, Lipska BK. Exaggerated MK-801-induced motor hyperactivity in rats with the neonatal lesion of the ventral hippocampus. Behav Pharmacology 11, 269-278, 2000.
20. Khaing ZZ, Weickert CS, Weinberger DR, Lipska BK. Differential DNA damage in response to the neonatal and adult excitotoxic hippocampal lesion in rats. Eur J Neurosci. 12 : 4424-4433, 2000.
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Updated May 6, 2003