Lidija Ivic - Academia.edu (original) (raw)

Papers by Lidija Ivic

Research paper thumbnail of Terpene Trilactones from Ginkgo biloba Are Antagonists of Cortical Glycine and GABAA Receptors

Journal of Biological Chemistry, Dec 1, 2003

Glycine and ␥-aminobutyric acid, type A (GABA A) receptors are members of the ligand-gated ion ch... more Glycine and ␥-aminobutyric acid, type A (GABA A) receptors are members of the ligand-gated ion channel superfamily that mediate inhibitory synaptic transmission in the adult central nervous system. During development, the activation of these receptors leads to membrane depolarization. Ligands for the two receptors have important implications both in disease therapy and as pharmacological tools. Terpene trilactones (ginkgolides and bilobalide) are unique constituents of Ginkgo biloba extracts that have various effects on the central nervous system. We have investigated the relative potency of these compounds on glycine and GABA A receptors. We find that most of the ginkgolides are selective and potent antagonists of the glycine receptor. Bilobalide, the single major component in G. biloba extracts, also reduces glycine-induced currents, although to a lesser extent. Both ginkgolides and bilobalide inhibit GABA A receptors, with bilobalide demonstrating a more potent effect. Additionally, we provide evidence that open channels are required for glycine receptor inhibition by ginkgolides. Finally, we employ molecular modeling to elucidate the similarities and differences in the structure of the terpene trilactones to account for the pharmacological properties of these compounds and demonstrate a striking similarity between ginkgolides and picrotoxinin, a GABA A and recombinant glycine ␣-homomeric receptor antagonist.

Research paper thumbnail of Hallucinogens Recruit Specific Cortical 5-HT2A Receptor-Mediated Signaling Pathways to Affect Behavior

Neuron, 2007

Hallucinogens, including mescaline, psilocybin, and lysergic acid diethylamide (LSD), profoundly ... more Hallucinogens, including mescaline, psilocybin, and lysergic acid diethylamide (LSD), profoundly affect perception, cognition, and mood. All known drugs of this class are 5-HT 2A receptor (2AR) agonists, yet closely related 2AR agonists such as lisuride lack comparable psychoactive properties. Why only certain 2AR agonists are hallucinogens and which neural circuits mediate their effects are poorly understood. By genetically expressing 2AR only in cortex, we show that 2AR-regulated pathways on cortical neurons are sufficient to mediate the signaling pattern and behavioral response to hallucinogens. Hallucinogenic and nonhallucinogenic 2AR agonists both regulate signaling in the same 2AR-expressing cortical neurons. However, the signaling and behavioral responses to the hallucinogens are distinct. While lisuride and LSD both act at 2AR expressed by cortex neurons to regulate phospholipase C, LSD responses also involve pertussis toxin-sensitive heterotrimeric G i/o proteins and Src. These studies identify the long-elusive neural and signaling mechanisms responsible for the unique effects of hallucinogens.

Research paper thumbnail of Adenoviral vector-mediated rescue of the OMP-null phenotype in vivo

Nature Neuroscience, 2000

The use of gene deletion by homologous recombination to determine gene or protein function has wi... more The use of gene deletion by homologous recombination to determine gene or protein function has wide application in vertebrate neurobiology. An ideal complement to gene deletion would be subsequent gene replacement to demonstrate re-acquisition of function. Here we used an adenoviral vector to replace the olfactory marker protein (OMP) gene in olfactory receptor neurons of adult OMP-null mice and demonstrated the subsequent re-acquisition of function. Our results show that short-term expression of OMP restores the kinetics of electrophysiological responses of OMP-null mice to those of the control phenotype. This adenoviral-mediated rescue of the OMP-null phenotype is consistent with involvement of OMP in olfactory transduction.

Research paper thumbnail of The Role of Neurogenic Astroglial Cells in the Developing and Adult Central Nervous System

Research paper thumbnail of Adenoviral vector-mediated rescue of the OMP-null phenotype in vivo

Nature neuroscience, 2000

The use of gene deletion by homologous recombination to determine gene or protein function has wi... more The use of gene deletion by homologous recombination to determine gene or protein function has wide application in vertebrate neurobiology. An ideal complement to gene deletion would be subsequent gene replacement to demonstrate re-acquisition of function. Here we used an adenoviral vector to replace the olfactory marker protein (OMP) gene in olfactory receptor neurons of adult OMP-null mice and demonstrated the subsequent re-acquisition of function. Our results show that short-term expression of OMP restores the kinetics of electrophysiological responses of OMP-null mice to those of the control phenotype. This adenoviral-mediated rescue of the OMP-null phenotype is consistent with involvement of OMP in olfactory transduction.

Research paper thumbnail of Terpene trilactones from Ginkgo biloba are antagonists of cortical glycine and GABA(A) receptors

The Journal of biological chemistry, Jan 5, 2003

Glycine and gamma-aminobutyric acid, type A (GABA(A)) receptors are members of the ligand-gated i... more Glycine and gamma-aminobutyric acid, type A (GABA(A)) receptors are members of the ligand-gated ion channel superfamily that mediate inhibitory synaptic transmission in the adult central nervous system. During development, the activation of these receptors leads to membrane depolarization. Ligands for the two receptors have important implications both in disease therapy and as pharmacological tools. Terpene trilactones (ginkgolides and bilobalide) are unique constituents of Ginkgo biloba extracts that have various effects on the central nervous system. We have investigated the relative potency of these compounds on glycine and GABA(A) receptors. We find that most of the ginkgolides are selective and potent antagonists of the glycine receptor. Bilobalide, the single major component in G. biloba extracts, also reduces glycine-induced currents, although to a lesser extent. Both ginkgolides and bilobalide inhibit GABA(A) receptors, with bilobalide demonstrating a more potent effect. Add...

Research paper thumbnail of Functional Expression of a Mammalian Odorant Receptor

Research paper thumbnail of Maintenance of helix pomatia neurons in simplified cell culture system

Comparative Biochemistry and Physiology Part C: Pharmacology, Toxicology and Endocrinology - COMP BIOCHEM PHYSIOL C PHARMACOL TOXICOL ENDOCRINOL, 1995

Helix pomatia neurons were successfully maintained in primary cell culture using the plant lectin... more Helix pomatia neurons were successfully maintained in primary cell culture using the plant lectin concanavalin A (con A) as the substrate. No additional factors such as hemolymph, conditioning medium or intact ganglia were used. Most of the isolated neurons including ones with large soma diameter (> 200 μm) adhered to the surface and nearly 100% of the adhered neurons sprouted and grew extensively branching neurites. By making connections with each other, the neurites belonging to several neurons often form extensive networks. Spontaneous bioelectrical activity was recorded in about 10% of neurons. In all other cells tested, action potentials similar to ones recorded in situ could be evoked by depolarization up to the 15th day after plating the neurons.

Research paper thumbnail of Calcium Waves Propagate through Radial Glial Cells and Modulate Proliferation in the Developing Neocortex

Neuron, 2004

of a single cell type potentially affecting both neuronal 3 Department of Pathology production an... more of a single cell type potentially affecting both neuronal 3 Department of Pathology production and overall cortical architecture. Since some Columbia University human developmental disorders associated with corti-New York, New York 10032 cal malformations involve defects in neuronal migration as well as neuronal production, radial glial cell modulation could have important clinical implications. More-Summary over, the unique morphology of the radial glial cell (Bentivoglio and Mazzarello, 1999), with a cell body in the The majority of neurons in the adult neocortex are

Research paper thumbnail of Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases

Nature Neuroscience, 2004

Precise patterns of cell division and migration are crucial to transform the neuroepithelium of t... more Precise patterns of cell division and migration are crucial to transform the neuroepithelium of the embryonic forebrain into the adult cerebral cortex. Using time-lapse imaging of clonal cells in rat cortex over several generations, we show here that neurons are generated in two proliferative zones by distinct patterns of division. Neurons arise directly from radial glial cells in the ventricular zone (VZ) and indirectly from intermediate progenitor cells in the subventricular zone (SVZ). Furthermore, newborn neurons do not migrate directly to the cortex; instead, most exhibit four distinct phases of migration, including a phase of retrograde movement toward the ventricle before migration to the cortical plate. These findings provide a comprehensive and new view of the dynamics of cortical neurogenesis and migration.

Research paper thumbnail of Characterization of Mice with Targeted Deletion of Glycine Receptor Alpha 2

Molecular and Cellular Biology, 2006

Glycine receptors are ligand-gated chloride channels that mediate inhibitory neurotransmission in... more Glycine receptors are ligand-gated chloride channels that mediate inhibitory neurotransmission in the adult nervous system. During development, glycine receptor alpha 2 (GlyRalpha2) is expressed in the retina, in the spinal cord, and throughout the brain. Within the cortex, GlyRalpha2 is expressed in immature cells and these receptors have been shown to be active and excitatory. In the developing retina, inhibition of glycine receptor activity prevents proper rod photoreceptor development. These data suggest that GlyRalpha2, the developmentally expressed glycine receptor, may play an important role in neuronal development. We have generated mice with a targeted deletion of glycine receptor alpha 2 (Glra2). Although these mice lack expression of GlyRalpha2, no gross morphological or molecular alterations were observed in the nervous system. In addition, the cerebral cortex does not appear to require glycine receptor activity for proper development, as Glra2 knockout mice did not show any electrophysiological responses to glycine.

Research paper thumbnail of Intracellular trafficking of a tagged and functional mammalian olfactory receptor

Journal of Neurobiology, 2002

Tagged G-protein-coupled receptors (GPCRs) have been used to facilitate intracellular visualizati... more Tagged G-protein-coupled receptors (GPCRs) have been used to facilitate intracellular visualization of these receptors. We have used a combination of adenoviral vector gene transfer and tagged olfactory receptors to help visualize mammalian olfactory receptor proteins in the normal olfactory epithelium of rats, and in cell culture. Three recombinant adenoviral vectors were generated carrying variously tagged versions of rat olfactory receptor I7. The constructs include an N-terminal Flag epitope tag (Flag:I7), enhanced green fluorescent protein (EGFP) fusion protein (EGFP:I7), and a C-terminal EGFP fusion (I7:EGFP). These receptor constructs were assayed in rat olfactory sensory neurons (OSNs) and in a heterologous system (HEK 293 cell line) for protein localization and functional expression. Functional expression of the tagged receptor proteins was tested by electroolfactogram (EOG) recordings in the infected rat olfactory epithelium, and by calcium imaging in single cells. Our results demonstrate that the I7:EGFP fusion protein and Flag:I7 are functionally expressed in OSNs while the EGFP:I7 fusion is not, probably due to inappropriate processing of the protein in the cells. These data suggest that a small epitope tag (Flag) at the N-terminus, or EGFP located at the C-terminus of the receptor, does not affect ligand binding or downstream signaling. In addition, both functional fusion proteins (Flag:I7 and I7:EGFP) are properly targeted to the plasma membrane of HEK 293 cells.

Research paper thumbnail of Hallucinogens Recruit Specific Cortical 5-HT2A Receptor-Mediated Signaling Pathways to Affect Behavior

Neuron, 2007

Hallucinogens, including mescaline, psilocybin, and lysergic acid diethylamide (LSD), profoundly ... more Hallucinogens, including mescaline, psilocybin, and lysergic acid diethylamide (LSD), profoundly affect perception, cognition, and mood. All known drugs of this class are 5-HT(2A) receptor (2AR) agonists, yet closely related 2AR agonists such as lisuride lack comparable psychoactive properties. Why only certain 2AR agonists are hallucinogens and which neural circuits mediate their effects are poorly understood. By genetically expressing 2AR only in cortex, we show that 2AR-regulated pathways on cortical neurons are sufficient to mediate the signaling pattern and behavioral response to hallucinogens. Hallucinogenic and nonhallucinogenic 2AR agonists both regulate signaling in the same 2AR-expressing cortical neurons. However, the signaling and behavioral responses to the hallucinogens are distinct. While lisuride and LSD both act at 2AR expressed by cortex neurons to regulate phospholipase C, LSD responses also involve pertussis toxin-sensitive heterotrimeric G(i/o) proteins and Src. These studies identify the long-elusive neural and signaling mechanisms responsible for the unique effects of hallucinogens.

Research paper thumbnail of Terpene Trilactones from Ginkgo biloba Are Antagonists of Cortical Glycine and GABAA Receptors

Journal of Biological Chemistry, Dec 1, 2003

Glycine and ␥-aminobutyric acid, type A (GABA A) receptors are members of the ligand-gated ion ch... more Glycine and ␥-aminobutyric acid, type A (GABA A) receptors are members of the ligand-gated ion channel superfamily that mediate inhibitory synaptic transmission in the adult central nervous system. During development, the activation of these receptors leads to membrane depolarization. Ligands for the two receptors have important implications both in disease therapy and as pharmacological tools. Terpene trilactones (ginkgolides and bilobalide) are unique constituents of Ginkgo biloba extracts that have various effects on the central nervous system. We have investigated the relative potency of these compounds on glycine and GABA A receptors. We find that most of the ginkgolides are selective and potent antagonists of the glycine receptor. Bilobalide, the single major component in G. biloba extracts, also reduces glycine-induced currents, although to a lesser extent. Both ginkgolides and bilobalide inhibit GABA A receptors, with bilobalide demonstrating a more potent effect. Additionally, we provide evidence that open channels are required for glycine receptor inhibition by ginkgolides. Finally, we employ molecular modeling to elucidate the similarities and differences in the structure of the terpene trilactones to account for the pharmacological properties of these compounds and demonstrate a striking similarity between ginkgolides and picrotoxinin, a GABA A and recombinant glycine ␣-homomeric receptor antagonist.

Research paper thumbnail of Hallucinogens Recruit Specific Cortical 5-HT2A Receptor-Mediated Signaling Pathways to Affect Behavior

Neuron, 2007

Hallucinogens, including mescaline, psilocybin, and lysergic acid diethylamide (LSD), profoundly ... more Hallucinogens, including mescaline, psilocybin, and lysergic acid diethylamide (LSD), profoundly affect perception, cognition, and mood. All known drugs of this class are 5-HT 2A receptor (2AR) agonists, yet closely related 2AR agonists such as lisuride lack comparable psychoactive properties. Why only certain 2AR agonists are hallucinogens and which neural circuits mediate their effects are poorly understood. By genetically expressing 2AR only in cortex, we show that 2AR-regulated pathways on cortical neurons are sufficient to mediate the signaling pattern and behavioral response to hallucinogens. Hallucinogenic and nonhallucinogenic 2AR agonists both regulate signaling in the same 2AR-expressing cortical neurons. However, the signaling and behavioral responses to the hallucinogens are distinct. While lisuride and LSD both act at 2AR expressed by cortex neurons to regulate phospholipase C, LSD responses also involve pertussis toxin-sensitive heterotrimeric G i/o proteins and Src. These studies identify the long-elusive neural and signaling mechanisms responsible for the unique effects of hallucinogens.

Research paper thumbnail of Adenoviral vector-mediated rescue of the OMP-null phenotype in vivo

Nature Neuroscience, 2000

The use of gene deletion by homologous recombination to determine gene or protein function has wi... more The use of gene deletion by homologous recombination to determine gene or protein function has wide application in vertebrate neurobiology. An ideal complement to gene deletion would be subsequent gene replacement to demonstrate re-acquisition of function. Here we used an adenoviral vector to replace the olfactory marker protein (OMP) gene in olfactory receptor neurons of adult OMP-null mice and demonstrated the subsequent re-acquisition of function. Our results show that short-term expression of OMP restores the kinetics of electrophysiological responses of OMP-null mice to those of the control phenotype. This adenoviral-mediated rescue of the OMP-null phenotype is consistent with involvement of OMP in olfactory transduction.

Research paper thumbnail of The Role of Neurogenic Astroglial Cells in the Developing and Adult Central Nervous System

Research paper thumbnail of Adenoviral vector-mediated rescue of the OMP-null phenotype in vivo

Nature neuroscience, 2000

The use of gene deletion by homologous recombination to determine gene or protein function has wi... more The use of gene deletion by homologous recombination to determine gene or protein function has wide application in vertebrate neurobiology. An ideal complement to gene deletion would be subsequent gene replacement to demonstrate re-acquisition of function. Here we used an adenoviral vector to replace the olfactory marker protein (OMP) gene in olfactory receptor neurons of adult OMP-null mice and demonstrated the subsequent re-acquisition of function. Our results show that short-term expression of OMP restores the kinetics of electrophysiological responses of OMP-null mice to those of the control phenotype. This adenoviral-mediated rescue of the OMP-null phenotype is consistent with involvement of OMP in olfactory transduction.

Research paper thumbnail of Terpene trilactones from Ginkgo biloba are antagonists of cortical glycine and GABA(A) receptors

The Journal of biological chemistry, Jan 5, 2003

Glycine and gamma-aminobutyric acid, type A (GABA(A)) receptors are members of the ligand-gated i... more Glycine and gamma-aminobutyric acid, type A (GABA(A)) receptors are members of the ligand-gated ion channel superfamily that mediate inhibitory synaptic transmission in the adult central nervous system. During development, the activation of these receptors leads to membrane depolarization. Ligands for the two receptors have important implications both in disease therapy and as pharmacological tools. Terpene trilactones (ginkgolides and bilobalide) are unique constituents of Ginkgo biloba extracts that have various effects on the central nervous system. We have investigated the relative potency of these compounds on glycine and GABA(A) receptors. We find that most of the ginkgolides are selective and potent antagonists of the glycine receptor. Bilobalide, the single major component in G. biloba extracts, also reduces glycine-induced currents, although to a lesser extent. Both ginkgolides and bilobalide inhibit GABA(A) receptors, with bilobalide demonstrating a more potent effect. Add...

Research paper thumbnail of Functional Expression of a Mammalian Odorant Receptor

Research paper thumbnail of Maintenance of helix pomatia neurons in simplified cell culture system

Comparative Biochemistry and Physiology Part C: Pharmacology, Toxicology and Endocrinology - COMP BIOCHEM PHYSIOL C PHARMACOL TOXICOL ENDOCRINOL, 1995

Helix pomatia neurons were successfully maintained in primary cell culture using the plant lectin... more Helix pomatia neurons were successfully maintained in primary cell culture using the plant lectin concanavalin A (con A) as the substrate. No additional factors such as hemolymph, conditioning medium or intact ganglia were used. Most of the isolated neurons including ones with large soma diameter (> 200 μm) adhered to the surface and nearly 100% of the adhered neurons sprouted and grew extensively branching neurites. By making connections with each other, the neurites belonging to several neurons often form extensive networks. Spontaneous bioelectrical activity was recorded in about 10% of neurons. In all other cells tested, action potentials similar to ones recorded in situ could be evoked by depolarization up to the 15th day after plating the neurons.

Research paper thumbnail of Calcium Waves Propagate through Radial Glial Cells and Modulate Proliferation in the Developing Neocortex

Neuron, 2004

of a single cell type potentially affecting both neuronal 3 Department of Pathology production an... more of a single cell type potentially affecting both neuronal 3 Department of Pathology production and overall cortical architecture. Since some Columbia University human developmental disorders associated with corti-New York, New York 10032 cal malformations involve defects in neuronal migration as well as neuronal production, radial glial cell modulation could have important clinical implications. More-Summary over, the unique morphology of the radial glial cell (Bentivoglio and Mazzarello, 1999), with a cell body in the The majority of neurons in the adult neocortex are

Research paper thumbnail of Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases

Nature Neuroscience, 2004

Precise patterns of cell division and migration are crucial to transform the neuroepithelium of t... more Precise patterns of cell division and migration are crucial to transform the neuroepithelium of the embryonic forebrain into the adult cerebral cortex. Using time-lapse imaging of clonal cells in rat cortex over several generations, we show here that neurons are generated in two proliferative zones by distinct patterns of division. Neurons arise directly from radial glial cells in the ventricular zone (VZ) and indirectly from intermediate progenitor cells in the subventricular zone (SVZ). Furthermore, newborn neurons do not migrate directly to the cortex; instead, most exhibit four distinct phases of migration, including a phase of retrograde movement toward the ventricle before migration to the cortical plate. These findings provide a comprehensive and new view of the dynamics of cortical neurogenesis and migration.

Research paper thumbnail of Characterization of Mice with Targeted Deletion of Glycine Receptor Alpha 2

Molecular and Cellular Biology, 2006

Glycine receptors are ligand-gated chloride channels that mediate inhibitory neurotransmission in... more Glycine receptors are ligand-gated chloride channels that mediate inhibitory neurotransmission in the adult nervous system. During development, glycine receptor alpha 2 (GlyRalpha2) is expressed in the retina, in the spinal cord, and throughout the brain. Within the cortex, GlyRalpha2 is expressed in immature cells and these receptors have been shown to be active and excitatory. In the developing retina, inhibition of glycine receptor activity prevents proper rod photoreceptor development. These data suggest that GlyRalpha2, the developmentally expressed glycine receptor, may play an important role in neuronal development. We have generated mice with a targeted deletion of glycine receptor alpha 2 (Glra2). Although these mice lack expression of GlyRalpha2, no gross morphological or molecular alterations were observed in the nervous system. In addition, the cerebral cortex does not appear to require glycine receptor activity for proper development, as Glra2 knockout mice did not show any electrophysiological responses to glycine.

Research paper thumbnail of Intracellular trafficking of a tagged and functional mammalian olfactory receptor

Journal of Neurobiology, 2002

Tagged G-protein-coupled receptors (GPCRs) have been used to facilitate intracellular visualizati... more Tagged G-protein-coupled receptors (GPCRs) have been used to facilitate intracellular visualization of these receptors. We have used a combination of adenoviral vector gene transfer and tagged olfactory receptors to help visualize mammalian olfactory receptor proteins in the normal olfactory epithelium of rats, and in cell culture. Three recombinant adenoviral vectors were generated carrying variously tagged versions of rat olfactory receptor I7. The constructs include an N-terminal Flag epitope tag (Flag:I7), enhanced green fluorescent protein (EGFP) fusion protein (EGFP:I7), and a C-terminal EGFP fusion (I7:EGFP). These receptor constructs were assayed in rat olfactory sensory neurons (OSNs) and in a heterologous system (HEK 293 cell line) for protein localization and functional expression. Functional expression of the tagged receptor proteins was tested by electroolfactogram (EOG) recordings in the infected rat olfactory epithelium, and by calcium imaging in single cells. Our results demonstrate that the I7:EGFP fusion protein and Flag:I7 are functionally expressed in OSNs while the EGFP:I7 fusion is not, probably due to inappropriate processing of the protein in the cells. These data suggest that a small epitope tag (Flag) at the N-terminus, or EGFP located at the C-terminus of the receptor, does not affect ligand binding or downstream signaling. In addition, both functional fusion proteins (Flag:I7 and I7:EGFP) are properly targeted to the plasma membrane of HEK 293 cells.

Research paper thumbnail of Hallucinogens Recruit Specific Cortical 5-HT2A Receptor-Mediated Signaling Pathways to Affect Behavior

Neuron, 2007

Hallucinogens, including mescaline, psilocybin, and lysergic acid diethylamide (LSD), profoundly ... more Hallucinogens, including mescaline, psilocybin, and lysergic acid diethylamide (LSD), profoundly affect perception, cognition, and mood. All known drugs of this class are 5-HT(2A) receptor (2AR) agonists, yet closely related 2AR agonists such as lisuride lack comparable psychoactive properties. Why only certain 2AR agonists are hallucinogens and which neural circuits mediate their effects are poorly understood. By genetically expressing 2AR only in cortex, we show that 2AR-regulated pathways on cortical neurons are sufficient to mediate the signaling pattern and behavioral response to hallucinogens. Hallucinogenic and nonhallucinogenic 2AR agonists both regulate signaling in the same 2AR-expressing cortical neurons. However, the signaling and behavioral responses to the hallucinogens are distinct. While lisuride and LSD both act at 2AR expressed by cortex neurons to regulate phospholipase C, LSD responses also involve pertussis toxin-sensitive heterotrimeric G(i/o) proteins and Src. These studies identify the long-elusive neural and signaling mechanisms responsible for the unique effects of hallucinogens.