- Email: [email protected]
155. Effects of lesion size, age and strain on behavioral responsiveness to hippocampal damage in mice
Thursday Abstracts
will review rodent studies examining the effects of antipsychotics on dopamine, serotonin, glutamate, GABA, and cholinergic receptor expression in limbic and motor circuits. These studies demonstrate that typical and atypical antipsychotics induce unique, region-specific patterns of receptor expression that may be the substrate of their beneficial clinical effects, as well as their side effects. Despite numerous studies to date, this literature is plagued with inconsistency, and it is difficult to reconcile all of the available data. Due to difficulties in making comparisons among the myriad experimental methodologies, and the pitfalls of attempting to generalize rodent data to human postmortem studies of schizophrenia, future studies on the effects of typical and atypical antipsychotics on receptor expression will need to: (1) simultaneously examine multiple neurotransmitter systems in the same sets of animals treated with typical and atypical antipsychotics; (2) examine multiple receptor subtypes of the same neurotransmitter system; (3) measure receptor expression in multiple, interconnected regions that comprise limbic and motor circuits; (4) measure receptor expression at multiple levels of gene organization.
BIOL PSYCHIATRY 2000;47:1S–173S
47S
antipsychotics revealed modulatory effects on dopaminergic pathways, but recent work has indicated effects upon multiple neurotransmitter systems. These receptor-mediated effects of antipsychotic medications converge on multiple signaling pathways. Modulation of cyclic nucleotide and phosphoinositide signaling has been directly linked to receptors targeted by antipsychotic medications. Despite the breadth of previous work, mechanistic formulation of the molecular effects of antipsychotic medications on signal transduction pathways has not been well synthesized. A review of the relevant literature for antipsychotic regulation of signaling processes will be presented. Specific differences between typical and atypical antipsychotics will be highlighted. Where relevant, molecular signaling processes will be linked to both therapeutic and adverse effects of antipsychotic medications. Finally, a model integrating different receptor families and signal transduction pathways with gene expression and clinical outcomes will be synthesized. This model will assist in the formulation of future studies examining the effects of typical and atypical antipsychotics on signaling pathways.
155. EFFECTS OF LESION SIZE, AGE AND STRAIN ON BEHAVIORAL RESPONSIVENESS TO HIPPOCAMPAL DAMAGE IN MICE K.A. Williams, M.G. Valentine, I. Lund, S. Tidman, D.R. Weinberger, B.K. Lipska Clinical Brain Disorders Branch, National Institute of Mental Health/ IRP, NIH, Bethesda, MD, 20892 We have previously studied behavioral changes following lesions of the ventral hippocampus in rats as a model of schizophrenia. These lesions produce a constellation of behavioral disruptions including hyperresponsiveness to dopamine agonists, increased vulnerability to stress, sensorimotor deficits and cognitive impairments. Neonatal lesions result in a different profile of behavioral abnormalities than similar lesions induced in adult animals. Some of these abnormal behaviors depend on the size of the lesion and on the rat strain. We have now investigated the effects of hippocampal damage in mice of various strains. Mice (ICR, C57BL/6 and A/J) were lesioned in the ventral hippocampus with ibotenic acid (0.15– 0.3 l, 1.5–3.0 g) on postnatal days 3 or 7 or in adulthood. Locomotor activity in response to novelty, amphetamine (2.5–7.5 mg/kg, i.p.) and MK-801 (0.1– 0.4 mg/kg s.c.) was monitored at various stages of development. Behavioral changes in adult lesioned animals were strain dependent. Several weeks after the lesion, adult lesioned ICR mice showed hyperactivity to amphetamine but no changes in novelty- or MK-801-induced behaviors as compared to controls. Adult lesioned A/J mice were hyperactive in response to novelty but not after amphetamine (2.5 or 5.0 mg/kg), whereas C57BL/6 mice expressed marked hyperlocomotion in both conditions. Neonatal lesions in ICR mice were dependent on the size of lesion and age at lesion. Mice lesioned on postnatal day 3 developed very small lesions that did not result in any behavioral changes at any testing age (day 25 and 50). In contrast, mice lesioned on postnatal day 7, showed significant hyperlocomotion to novelty, amphetamine and MK-801. Our data indicate that the consequences of hippocampal damage depend on many factors, including genetic strain, size of lesion and age at lesion.
156. ANTIPSYCHOTIC REGULATION OF SIGNAL TRANSDUCTION PATHWAYS R.E. Smith, D.J. Healy, J.H. Meador-Woodruff Mental Health Research Institute and Department of Psychiatry, University of Michigan, Ann Arbor, MI 48109 Despite forty years of investigation, the mechanism of action of antipsychotic medications is not well known. The initial characterization of
157. EXPRESSION OF EXON 22-CONTAINING NR1 NMDA RECEPTOR SUBUNITS IN THALAMUS IN SCHIZOPHRENIA S.M. Clinton, D.J. Healy, R.E. Smith, V. Haroutunian, K.L. Davis, S.J. Watson, J.H. Meador-Woodruff Mental Health Research Institute and Dept. of Psychiatry, University of Michigan, Ann Arbor, MI 48109 Evidence suggests that abnormal glutamatergic transmission may be involved in the pathophysiology of schizophrenia since phencyclidine (PCP), an antagonist of the NMDA receptor, produces symptoms akin to positive and negative schizophrenic symptoms. Normal glutamatergic transmission relies on the presence of various receptors, co-factors, and other proteins such as amino acid transporters and receptor anchoring proteins. Anchoring proteins insert glutamate receptors in the synaptic membrane, facilitating receptor interactions with various intracellular components. Alterations of the NMDA receptor-anchoring protein interaction may affect normal receptor function. Specific anchoring proteins are associated with specific regions of the NMDA NR1 subunit, coded in exon 21 and/or 22. We have previously reported abnormal expression of total NR1 mRNA levels in schizophrenic thalamus. Given the relationship of anchoring proteins and the 3⬘ exons of this gene, we hypothesized that this abnormality may be specifically associated with exon 21 or 22 containing isoforms of the NR1 subunit. Using in situ hybridization we examined exon 22 mRNA expression in postmortem thalamic tissue from 13 schizophrenic and 9 control subjects, identifying six thalamic nuclei: anterior, dorsomedial, lateral dorsal, central medial, reticular, and nuclei of the ventral tier. Preliminary data indicate that there is diminished exon 22 mRNA expression in schizophrenic thalamus compared to controls. Subsequent studies will examine expression of exon 5 and 21 mRNA in these regions. These data reveal a reduction in exon 22 containing isoforms of the NR1 subunit in schizophrenic thalamus, and may suggest a physiological basis for diminished activity of the NMDA receptor in schizophrenia.
will review rodent studies examining the effects of antipsychotics on dopamine, serotonin, glutamate, GABA, and cholinergic receptor expression in limbic and motor circuits. These studies demonstrate that typical and atypical antipsychotics induce unique, region-specific patterns of receptor expression that may be the substrate of their beneficial clinical effects, as well as their side effects. Despite numerous studies to date, this literature is plagued with inconsistency, and it is difficult to reconcile all of the available data. Due to difficulties in making comparisons among the myriad experimental methodologies, and the pitfalls of attempting to generalize rodent data to human postmortem studies of schizophrenia, future studies on the effects of typical and atypical antipsychotics on receptor expression will need to: (1) simultaneously examine multiple neurotransmitter systems in the same sets of animals treated with typical and atypical antipsychotics; (2) examine multiple receptor subtypes of the same neurotransmitter system; (3) measure receptor expression in multiple, interconnected regions that comprise limbic and motor circuits; (4) measure receptor expression at multiple levels of gene organization.
BIOL PSYCHIATRY 2000;47:1S–173S
47S
antipsychotics revealed modulatory effects on dopaminergic pathways, but recent work has indicated effects upon multiple neurotransmitter systems. These receptor-mediated effects of antipsychotic medications converge on multiple signaling pathways. Modulation of cyclic nucleotide and phosphoinositide signaling has been directly linked to receptors targeted by antipsychotic medications. Despite the breadth of previous work, mechanistic formulation of the molecular effects of antipsychotic medications on signal transduction pathways has not been well synthesized. A review of the relevant literature for antipsychotic regulation of signaling processes will be presented. Specific differences between typical and atypical antipsychotics will be highlighted. Where relevant, molecular signaling processes will be linked to both therapeutic and adverse effects of antipsychotic medications. Finally, a model integrating different receptor families and signal transduction pathways with gene expression and clinical outcomes will be synthesized. This model will assist in the formulation of future studies examining the effects of typical and atypical antipsychotics on signaling pathways.
155. EFFECTS OF LESION SIZE, AGE AND STRAIN ON BEHAVIORAL RESPONSIVENESS TO HIPPOCAMPAL DAMAGE IN MICE K.A. Williams, M.G. Valentine, I. Lund, S. Tidman, D.R. Weinberger, B.K. Lipska Clinical Brain Disorders Branch, National Institute of Mental Health/ IRP, NIH, Bethesda, MD, 20892 We have previously studied behavioral changes following lesions of the ventral hippocampus in rats as a model of schizophrenia. These lesions produce a constellation of behavioral disruptions including hyperresponsiveness to dopamine agonists, increased vulnerability to stress, sensorimotor deficits and cognitive impairments. Neonatal lesions result in a different profile of behavioral abnormalities than similar lesions induced in adult animals. Some of these abnormal behaviors depend on the size of the lesion and on the rat strain. We have now investigated the effects of hippocampal damage in mice of various strains. Mice (ICR, C57BL/6 and A/J) were lesioned in the ventral hippocampus with ibotenic acid (0.15– 0.3 l, 1.5–3.0 g) on postnatal days 3 or 7 or in adulthood. Locomotor activity in response to novelty, amphetamine (2.5–7.5 mg/kg, i.p.) and MK-801 (0.1– 0.4 mg/kg s.c.) was monitored at various stages of development. Behavioral changes in adult lesioned animals were strain dependent. Several weeks after the lesion, adult lesioned ICR mice showed hyperactivity to amphetamine but no changes in novelty- or MK-801-induced behaviors as compared to controls. Adult lesioned A/J mice were hyperactive in response to novelty but not after amphetamine (2.5 or 5.0 mg/kg), whereas C57BL/6 mice expressed marked hyperlocomotion in both conditions. Neonatal lesions in ICR mice were dependent on the size of lesion and age at lesion. Mice lesioned on postnatal day 3 developed very small lesions that did not result in any behavioral changes at any testing age (day 25 and 50). In contrast, mice lesioned on postnatal day 7, showed significant hyperlocomotion to novelty, amphetamine and MK-801. Our data indicate that the consequences of hippocampal damage depend on many factors, including genetic strain, size of lesion and age at lesion.
156. ANTIPSYCHOTIC REGULATION OF SIGNAL TRANSDUCTION PATHWAYS R.E. Smith, D.J. Healy, J.H. Meador-Woodruff Mental Health Research Institute and Department of Psychiatry, University of Michigan, Ann Arbor, MI 48109 Despite forty years of investigation, the mechanism of action of antipsychotic medications is not well known. The initial characterization of
157. EXPRESSION OF EXON 22-CONTAINING NR1 NMDA RECEPTOR SUBUNITS IN THALAMUS IN SCHIZOPHRENIA S.M. Clinton, D.J. Healy, R.E. Smith, V. Haroutunian, K.L. Davis, S.J. Watson, J.H. Meador-Woodruff Mental Health Research Institute and Dept. of Psychiatry, University of Michigan, Ann Arbor, MI 48109 Evidence suggests that abnormal glutamatergic transmission may be involved in the pathophysiology of schizophrenia since phencyclidine (PCP), an antagonist of the NMDA receptor, produces symptoms akin to positive and negative schizophrenic symptoms. Normal glutamatergic transmission relies on the presence of various receptors, co-factors, and other proteins such as amino acid transporters and receptor anchoring proteins. Anchoring proteins insert glutamate receptors in the synaptic membrane, facilitating receptor interactions with various intracellular components. Alterations of the NMDA receptor-anchoring protein interaction may affect normal receptor function. Specific anchoring proteins are associated with specific regions of the NMDA NR1 subunit, coded in exon 21 and/or 22. We have previously reported abnormal expression of total NR1 mRNA levels in schizophrenic thalamus. Given the relationship of anchoring proteins and the 3⬘ exons of this gene, we hypothesized that this abnormality may be specifically associated with exon 21 or 22 containing isoforms of the NR1 subunit. Using in situ hybridization we examined exon 22 mRNA expression in postmortem thalamic tissue from 13 schizophrenic and 9 control subjects, identifying six thalamic nuclei: anterior, dorsomedial, lateral dorsal, central medial, reticular, and nuclei of the ventral tier. Preliminary data indicate that there is diminished exon 22 mRNA expression in schizophrenic thalamus compared to controls. Subsequent studies will examine expression of exon 5 and 21 mRNA in these regions. These data reveal a reduction in exon 22 containing isoforms of the NR1 subunit in schizophrenic thalamus, and may suggest a physiological basis for diminished activity of the NMDA receptor in schizophrenia.