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Functional alterations in the olfactory bulb of the staggerer mutant mouse
Neuroscience Letters 280 (2000) 1±4 www.elsevier.com/locate/neulet
Functional alterations in the olfactory bulb of the staggerer mutant mouse Vincent Michel a,*, Zohreh Monnier a, Jean-Marie Guastavino b, Alain Propper a, FrancËois Math a a
b
Laboratoire de Neurosciences, EA 1063, Universite de Franche-ComteÂ, Place Leclerc, 25030 BesancËon, France Laboratoire de Biologie du Comportement, CNRS, Universite Nancy 1, Faculte des Sciences, 54500 Vandoeuvre-les-Nancy, France Received 2 August 1999; received in revised form 19 November 1999; accepted 25 November 1999
Abstract Putative alterations of the functional activity in the staggerer mutant mouse olfactory bulb neuronal network have been studied by recording odor induced evoked ®eld potentials (EFP) in the mitral cells layer. In standard conditions, the main feature observed in mutants was a signi®cant increase in latency preceding the functional response of the mitral cells to the odorant. In these animals, all parameters of the average EFP were widely modi®ed when compared with those recorded in wild mice. Amplitudes and most of the duration of the EFP phases were signi®cantly decreased. Functional alterations were discussed according to the structural disorganization previously described in staggerer mutant mouse olfactory bulb. q 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Staggerer mutant; Olfactory bulb; Functional activity; Evoked ®eld potentials; Mouse
The olfactory system is well known to present unique capacities of continuous neuronal renewal in the olfactory epithelium. This goes along with a constant synaptic plasticity occurring between new sensory neuron endings and the main neurons of the olfactory bulbs (OB). Nevertheless, various brain diseases appear to have a direct effect [8,15] on this extraordinary plasticity property whose mechanisms still remain poorly understood. An important current challenge is to develop an animal model displaying alterations in these capacities of neuronal plasticity. The staggerer mutant mouse, steming from the C57BL/6J strain, was described by Sidman et al., in 1962 [16] and could be a good model for these studies. Homozygous for the staggerer mutation (sg) display a small size, mild tremor, hypotonia and staggering gait [16]. Staggerer mutation is due to RORa gene alteration [10,17] and induces a wide variety of structural, functional and behavioral disorders. The cerebellum is particularly affected by the mutation and the cerebellar cortex is underdeveloped with a de®ciency of granule cells and Purkinje cells [9,18]. Moreover, in staggerer mutants, such events occur also in the olfactory system [2,4]. It was shown recently in our * Corresponding author. Tel.: 133-03-81-665-732; fax: 133-0381-665-754. E-mail address: [email protected] (V. Michel); [email protected] (V. Michel)
laboratory [11] that staggerer mutation yields important alterations in the cytomorphological organization of the OB. Due to the importance of the neuronal interactions occurring inside the OB, such alterations could lead to a failure in the neuronal input processing. So in the present work, we intend to seek how the staggerer mutation impairs OB functional activity. For that purpose, we have chosen to study variations in the global activity of mitral cells, which are the main neurons of the OB, by recording the evoked ®eld potential (EFP) induced at their level by odorant stimulations. The analysis of EFP averages allows to follow the evolution of the mitral cells and interneuronal interactions during their activation by odorants [3,7,12]. These EFPs are also the result of self-excitations and cross-excitations between adjacent mitral cells receiving neuronal inputs from the same glomeruli [1,14]. EFP recordings were carried out on 15 2-month-old homozygous staggerer (sg/sg) mutant mice (a gift from Prof. J.M. Guastavino, Nancy, France), reared in our laboratory. As suggested by previous works [13,19], control animals were age-related C57BL/6J mice bred in our laboratory. Miceanaesthetized byi.p. injection of chloral hydrate 0.3 M (0.8 ml/100 g) were immobilized in a stereotaxic apparatus and a hole was drilled through the skull in the dorso-medial area of the OB. Odorant stimuli, consisting in amyl alcohol
0304-3940/00/$ - see front matter q 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S03 04 - 394 0( 9 9) 00 94 5- 3
2
V. Michel et al. / Neuroscience Letters 280 (2000) 1±4
Fig. 1. Control of the recording electrode tip location level by using Lucifer Yellow dye. Ionophoresis micropipettes and tungsten electrode were glued tip against tip. After each recording series of EFP, an ejection current was applied between a reference micropipette ®lled with NaCl solution and another one ®lled with the Lucifer Yellow solution. EPL, external plexiform layer; IPL, internal plexiform layer; MCL, mitral cells layer. Scale bar: 35 mm.
(SIGMA) pulses were delivered by means of an olfactometer. Odor-induced EFP were obtained from tungsten electrodes (20 mm in diameter at the tip) (WPI) and lowered into the mitral cells layer using stereotaxic coordinates. The soma
level was typically found at a depth of 350 mm in the C57BL/6J adult mice [5] and 250 mm in the staggerer mutants [11]. Potentials were ampli®ed using a DAM 70 ampli®er (WPI) and stored on a computer using a CIO-DAS 1600 data acquisition system (COMPUTER BOARD). After each recording series, an aqueous solution of Lucifer Yellow (0.1 g/l) was ejected by ionophoresis in order to provide a histological control of the electrode tip location level. Ionophoresis pipette was glued to the tungsten electrode in such a manner that the intertip distance was no more than 10 mm. At the end of the experiments, animals were sacri®ced and the olfactory bulbs were removed, ®xed with a Bouin± Hollande solution and some 6 mm thick slices were made. The slices were observed under ¯uorescence microscopy in order to check electrode tip location level with Lucifer Yellow dye (Fig. 1). Potential averaging and analyses were made using a speci®c software (ACQUIS1-CNRS, France). The EFP can be divided into two main components: N1 and N2, in which two phases: p1, n1, and p2, n2 may be recognized (Fig. 2) [12]. All the parameters of the EFP phases were compared by using the non-parametric Mann±Whitney statistical test. Individual recordings and EFP averages showed some signi®cant variations between OB functional activities of wild and mutant mice (Fig. 2). The main feature observed in mutants was a highly significant (P , 0:01) increase in latency preceding the functional response of the mitral cells (66% increase, with
Fig. 2. Examples of individual odor-induced EFPs recorded in mitral cells layers of wild mice (A) and staggerer mutant mice (C). Additions of EFP series registered, respectively in 15 animals of each strains allowed to work out averaged EFPs in wild (B) and mutant (D) mice. N1 and N2 components and p1, n1 and p2, n2 phases making up a EFP are shown on the graphic representation of the wild mice averaged EFP. `L' indicates the latency average.
V. Michel et al. / Neuroscience Letters 280 (2000) 1±4
20.4 ^ 3 ms in mutants (n 15) vs. 12 ^ 1 ms in wild mice (n 15) (Fig. 3). The latency would represent the delay necessary to carry the olfactory signal along axonal pathways from the receptor cells to OB. As previous studies have demonstrated that both the olfactory nerves and nervous layer are well preserved in staggerer mutant mice [11], the marked heterogeneity and disorganization observed in the glomerular layer of the mutant OB could be, thus, the primary cause of the EFP latency increase. The relations between olfactory nerve endings and mitral cells occurring in glomeruli could be, thus, strongly impaired, with a failure in the neuronal input to discriminate olfactory signals received from the sensory cells. This would lead to an increase in latency. Those structural alterations could also explain the very
3
signi®cant (P , 0:01) variation observed in N1 component amplitude of the mutant mice EFP average (Figs. 2 and 3). Indeed, N1 may represent the depolarization of the mitral cell apical dendrites by the olfactory nerve endings within the glomeruli [12]. In mutant mice, the amplitudes of p1 (1 ^ 0.1 mV in mutants vs. 1.5 ^ 0.2 mV in wild mice) and n1 (0.9 ^ 0.2 mV in mutants vs. 2.35 ^ 0.3 mV in wild mice) phases reached only 67 and 37% of those EFP amplitudes registered in wild mice (Fig. 3). Moreover, staggerer mutation leads to a very signi®cant (P , 0:01) decrease in the amplitude of the N2 component (Figs. 2 and 3). In the mutants, the averaged amplitudes of p2 (1.1 ^ 0.2 mV in mutants vs. 2.44 ^ 0.2 mV in wild mice) and n2 (1 ^ 0.1 mV in mutants vs. 2.2 ^ 0.2 mV in wild mice) phases were, respectively, 55 and 55.5% of those recorded in wild mice (Fig. 3).
Fig. 3. Averaged parameters (durations and amplitudes) of the EFP phases depending on mice genotypes (w/w for wild mice (n 15) and sg/sg for staggerer mutant mice (n 15)) (a). Graphic representation of the variations and standard errors of the EFP averaged phases amplitudes and durations obtained in wild mice (w) and staggerer mutant mice (sg) (b).
4
V. Michel et al. / Neuroscience Letters 280 (2000) 1±4
These last phases are related with phenomenons occurring in the deeper layers of the OB [3,7,12], such as dendrodendritic synaptic exchanges between secondary dendrites of mitral cells and granular cells dendrites, or cross-excitations between mitral cells. Previous work has, therefore, established that both the overall size of the OB and the number of mitral cells are very signi®cantly reduced in staggerer mutant mice [11]. This could, thus, explain decreases in amplitudes and durations of the EFPs components recorded at the mitral cells level of mutants OB (Fig. 3). However, we don't know whether dendrodendritic synaptic density is affected by staggerer mutation. It could be possible that, such as in the Purkinje cell degeneration (PCD) mutant, following mitral cell loss, many granule cell spines survive denervation and establish new reciprocal dendrodendritic synapses at available sites on deep tufted cells, other neurons of the OB [6]. Our results have shown that structural disorders due to the staggerer mutation result also in great and signi®cant variations in the control of the functional activity of the olfactory system, mostly in the OB, ®rst level of the neuronal input integration. The staggerer mutant mouse could, thus, allow further investigations to explore the functional plasticity occurring in the olfactory system. [1] Aroniadou Anderjaska, V., Ennis, M. and Shipley, M.T., Dendrodendritic recurrent excitation in mitral cells of the rat olfactory bulb. J. Neurophysiol., 82 (1999) 489±494. [2] Deiss, V. and Baudoin, C., Hyposmia for butanol and vanillin in mutant staggerer male mice. Physiol. Behav., 61 (1997) 209±213. [3] Duchamp-Viret, P., Duchamp, A. and Chaput, M., GABAergic control of odor-induced activity in the frog olfactory bulb: electrophysiological study with picrotoxin and bicuculline. Neuroscience, 53 (1993) 111±120. [4] FeÂron, C. and Baudoin, C., Social isolation induces preference for odours of oestrous females in sexually naive male staggerer mutant mice. Chem. Senses, 23 (1998) 119±121. [5] Franklin, K.B.J. and Paxinos, G., The Mouse Brain in Stereotaxic Coordinates, Academic Press, New York, 1997. [6] Greer, C.A. and HalaÁsz, N., Plasticity of dendrodendritic microcircuits following mitral cell loss in the olfactory
[7] [8] [9] [10]
[11]
[12]
[13]
[14] [15] [16] [17]
[18] [19]
bulb of the murine mutant Purkinje cell degeneration. J. Comp. Neurol., 256 (1987) 284±298. Jiang, T. and Holley, A., Some properties of receptive ®elds of olfactory mitral/tufted cells in the frog. J. Neurophysiol., 68 (1992) 726±733. Kopala, L.C., Good, K.P., Koczapski, A.B. and Honer, W.G., Olfactory de®cits in patients with schizophrenia and severe polydipsia. Biol. Psychiatry, 43 (1998) 497±502. Landis, D.M. and Sidman, R.L., Electron microscopic analysis of postnatal histogenesis in the cerebellar cortex of staggerer mutant mice. J. Comp. Neurol., 179 (1978) 831±863. Matysiak Scholze, U. and Nehls, M., The structural integrity of ROR alpha isoforms is mutated in staggerer mice: cerebellar coexpression of ROR alpha1 and ROR alpha4. Genomics, 43 (1997) 78±84. Monnier, Z., Bahjaoui-Bouhaddi, M., Bride, J., Bride, M., Math, F. and Propper, A., Structural and immunohistological modi®cations in the olfactory bulb of the staggerer mutant mouse. Biol. Cell, 91 (1999) 29±44. Mouly, A.M., Elaagouby, A. and Ravel, N., A study of the effects of noradrenaline in the rat olfactory bulb using evoked ®eld potential response. Brain Res., 681 (1995) 47± 57. Nakagawa, S., Watanabe, M. and Inoue, Y., Altered gene expression of the N-Methyl-D-aspartate receptor channel subunits in Purkinje cells of the staggerer mutant mouse. Eur. J. Neurosciences, 8 (1996) 2644±2651. Nicoll, R.A. and Jahr, C.E., Self-excitation of olfactory bulb neurones. Nature, 296 (1982) 441±444. Nordin, S., Almkvist, O., Berglund, B. and Wahlund, L.O., Olfactory dysfunction for pyridine and dementia progression in Alzheimer disease. Arch. Neurol., 54 (1997) 993±998. Sidman, R., Lane, P. and Dickie, M., Staggerer: a new mutation in the mouse affecting cerebellum. Science, 137 (1962) 610±612. Steinmayr, M., AndreeÂ, E., Conquet, F., Rondi Reig, L., Delhaye-Bouchaud, N., Auclair, N., Daniel, H., CreeÂpel, F., Mariani, J., Sotelo, C. and Becker-AndreeÂ, M., Staggerer phenotype in retinoid-related orphan receptor alpha-de®cient mice. Proc. Natl. Acad. Sci. USA, 95 (1998) 3960± 3965. Yoon, C.H., Developmental mechanism for changes in cerebellum of staggerer mouse, a neurological mutant of genetic origin. Neurology, 22 (1972) 743±754. Zanjani, H.S., Herrup, K., Guastavino, J.M., DelhayeBouchaud, N. and Mariani, J., Developmental studies of the inferior olivary nucleus in staggerer mutant mice. Dev. Brain Res., 82 (1994) 18±28.
Functional alterations in the olfactory bulb of the staggerer mutant mouse Vincent Michel a,*, Zohreh Monnier a, Jean-Marie Guastavino b, Alain Propper a, FrancËois Math a a
b
Laboratoire de Neurosciences, EA 1063, Universite de Franche-ComteÂ, Place Leclerc, 25030 BesancËon, France Laboratoire de Biologie du Comportement, CNRS, Universite Nancy 1, Faculte des Sciences, 54500 Vandoeuvre-les-Nancy, France Received 2 August 1999; received in revised form 19 November 1999; accepted 25 November 1999
Abstract Putative alterations of the functional activity in the staggerer mutant mouse olfactory bulb neuronal network have been studied by recording odor induced evoked ®eld potentials (EFP) in the mitral cells layer. In standard conditions, the main feature observed in mutants was a signi®cant increase in latency preceding the functional response of the mitral cells to the odorant. In these animals, all parameters of the average EFP were widely modi®ed when compared with those recorded in wild mice. Amplitudes and most of the duration of the EFP phases were signi®cantly decreased. Functional alterations were discussed according to the structural disorganization previously described in staggerer mutant mouse olfactory bulb. q 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Staggerer mutant; Olfactory bulb; Functional activity; Evoked ®eld potentials; Mouse
The olfactory system is well known to present unique capacities of continuous neuronal renewal in the olfactory epithelium. This goes along with a constant synaptic plasticity occurring between new sensory neuron endings and the main neurons of the olfactory bulbs (OB). Nevertheless, various brain diseases appear to have a direct effect [8,15] on this extraordinary plasticity property whose mechanisms still remain poorly understood. An important current challenge is to develop an animal model displaying alterations in these capacities of neuronal plasticity. The staggerer mutant mouse, steming from the C57BL/6J strain, was described by Sidman et al., in 1962 [16] and could be a good model for these studies. Homozygous for the staggerer mutation (sg) display a small size, mild tremor, hypotonia and staggering gait [16]. Staggerer mutation is due to RORa gene alteration [10,17] and induces a wide variety of structural, functional and behavioral disorders. The cerebellum is particularly affected by the mutation and the cerebellar cortex is underdeveloped with a de®ciency of granule cells and Purkinje cells [9,18]. Moreover, in staggerer mutants, such events occur also in the olfactory system [2,4]. It was shown recently in our * Corresponding author. Tel.: 133-03-81-665-732; fax: 133-0381-665-754. E-mail address: [email protected] (V. Michel); [email protected] (V. Michel)
laboratory [11] that staggerer mutation yields important alterations in the cytomorphological organization of the OB. Due to the importance of the neuronal interactions occurring inside the OB, such alterations could lead to a failure in the neuronal input processing. So in the present work, we intend to seek how the staggerer mutation impairs OB functional activity. For that purpose, we have chosen to study variations in the global activity of mitral cells, which are the main neurons of the OB, by recording the evoked ®eld potential (EFP) induced at their level by odorant stimulations. The analysis of EFP averages allows to follow the evolution of the mitral cells and interneuronal interactions during their activation by odorants [3,7,12]. These EFPs are also the result of self-excitations and cross-excitations between adjacent mitral cells receiving neuronal inputs from the same glomeruli [1,14]. EFP recordings were carried out on 15 2-month-old homozygous staggerer (sg/sg) mutant mice (a gift from Prof. J.M. Guastavino, Nancy, France), reared in our laboratory. As suggested by previous works [13,19], control animals were age-related C57BL/6J mice bred in our laboratory. Miceanaesthetized byi.p. injection of chloral hydrate 0.3 M (0.8 ml/100 g) were immobilized in a stereotaxic apparatus and a hole was drilled through the skull in the dorso-medial area of the OB. Odorant stimuli, consisting in amyl alcohol
0304-3940/00/$ - see front matter q 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S03 04 - 394 0( 9 9) 00 94 5- 3
2
V. Michel et al. / Neuroscience Letters 280 (2000) 1±4
Fig. 1. Control of the recording electrode tip location level by using Lucifer Yellow dye. Ionophoresis micropipettes and tungsten electrode were glued tip against tip. After each recording series of EFP, an ejection current was applied between a reference micropipette ®lled with NaCl solution and another one ®lled with the Lucifer Yellow solution. EPL, external plexiform layer; IPL, internal plexiform layer; MCL, mitral cells layer. Scale bar: 35 mm.
(SIGMA) pulses were delivered by means of an olfactometer. Odor-induced EFP were obtained from tungsten electrodes (20 mm in diameter at the tip) (WPI) and lowered into the mitral cells layer using stereotaxic coordinates. The soma
level was typically found at a depth of 350 mm in the C57BL/6J adult mice [5] and 250 mm in the staggerer mutants [11]. Potentials were ampli®ed using a DAM 70 ampli®er (WPI) and stored on a computer using a CIO-DAS 1600 data acquisition system (COMPUTER BOARD). After each recording series, an aqueous solution of Lucifer Yellow (0.1 g/l) was ejected by ionophoresis in order to provide a histological control of the electrode tip location level. Ionophoresis pipette was glued to the tungsten electrode in such a manner that the intertip distance was no more than 10 mm. At the end of the experiments, animals were sacri®ced and the olfactory bulbs were removed, ®xed with a Bouin± Hollande solution and some 6 mm thick slices were made. The slices were observed under ¯uorescence microscopy in order to check electrode tip location level with Lucifer Yellow dye (Fig. 1). Potential averaging and analyses were made using a speci®c software (ACQUIS1-CNRS, France). The EFP can be divided into two main components: N1 and N2, in which two phases: p1, n1, and p2, n2 may be recognized (Fig. 2) [12]. All the parameters of the EFP phases were compared by using the non-parametric Mann±Whitney statistical test. Individual recordings and EFP averages showed some signi®cant variations between OB functional activities of wild and mutant mice (Fig. 2). The main feature observed in mutants was a highly significant (P , 0:01) increase in latency preceding the functional response of the mitral cells (66% increase, with
Fig. 2. Examples of individual odor-induced EFPs recorded in mitral cells layers of wild mice (A) and staggerer mutant mice (C). Additions of EFP series registered, respectively in 15 animals of each strains allowed to work out averaged EFPs in wild (B) and mutant (D) mice. N1 and N2 components and p1, n1 and p2, n2 phases making up a EFP are shown on the graphic representation of the wild mice averaged EFP. `L' indicates the latency average.
V. Michel et al. / Neuroscience Letters 280 (2000) 1±4
20.4 ^ 3 ms in mutants (n 15) vs. 12 ^ 1 ms in wild mice (n 15) (Fig. 3). The latency would represent the delay necessary to carry the olfactory signal along axonal pathways from the receptor cells to OB. As previous studies have demonstrated that both the olfactory nerves and nervous layer are well preserved in staggerer mutant mice [11], the marked heterogeneity and disorganization observed in the glomerular layer of the mutant OB could be, thus, the primary cause of the EFP latency increase. The relations between olfactory nerve endings and mitral cells occurring in glomeruli could be, thus, strongly impaired, with a failure in the neuronal input to discriminate olfactory signals received from the sensory cells. This would lead to an increase in latency. Those structural alterations could also explain the very
3
signi®cant (P , 0:01) variation observed in N1 component amplitude of the mutant mice EFP average (Figs. 2 and 3). Indeed, N1 may represent the depolarization of the mitral cell apical dendrites by the olfactory nerve endings within the glomeruli [12]. In mutant mice, the amplitudes of p1 (1 ^ 0.1 mV in mutants vs. 1.5 ^ 0.2 mV in wild mice) and n1 (0.9 ^ 0.2 mV in mutants vs. 2.35 ^ 0.3 mV in wild mice) phases reached only 67 and 37% of those EFP amplitudes registered in wild mice (Fig. 3). Moreover, staggerer mutation leads to a very signi®cant (P , 0:01) decrease in the amplitude of the N2 component (Figs. 2 and 3). In the mutants, the averaged amplitudes of p2 (1.1 ^ 0.2 mV in mutants vs. 2.44 ^ 0.2 mV in wild mice) and n2 (1 ^ 0.1 mV in mutants vs. 2.2 ^ 0.2 mV in wild mice) phases were, respectively, 55 and 55.5% of those recorded in wild mice (Fig. 3).
Fig. 3. Averaged parameters (durations and amplitudes) of the EFP phases depending on mice genotypes (w/w for wild mice (n 15) and sg/sg for staggerer mutant mice (n 15)) (a). Graphic representation of the variations and standard errors of the EFP averaged phases amplitudes and durations obtained in wild mice (w) and staggerer mutant mice (sg) (b).
4
V. Michel et al. / Neuroscience Letters 280 (2000) 1±4
These last phases are related with phenomenons occurring in the deeper layers of the OB [3,7,12], such as dendrodendritic synaptic exchanges between secondary dendrites of mitral cells and granular cells dendrites, or cross-excitations between mitral cells. Previous work has, therefore, established that both the overall size of the OB and the number of mitral cells are very signi®cantly reduced in staggerer mutant mice [11]. This could, thus, explain decreases in amplitudes and durations of the EFPs components recorded at the mitral cells level of mutants OB (Fig. 3). However, we don't know whether dendrodendritic synaptic density is affected by staggerer mutation. It could be possible that, such as in the Purkinje cell degeneration (PCD) mutant, following mitral cell loss, many granule cell spines survive denervation and establish new reciprocal dendrodendritic synapses at available sites on deep tufted cells, other neurons of the OB [6]. Our results have shown that structural disorders due to the staggerer mutation result also in great and signi®cant variations in the control of the functional activity of the olfactory system, mostly in the OB, ®rst level of the neuronal input integration. The staggerer mutant mouse could, thus, allow further investigations to explore the functional plasticity occurring in the olfactory system. [1] Aroniadou Anderjaska, V., Ennis, M. and Shipley, M.T., Dendrodendritic recurrent excitation in mitral cells of the rat olfactory bulb. J. Neurophysiol., 82 (1999) 489±494. [2] Deiss, V. and Baudoin, C., Hyposmia for butanol and vanillin in mutant staggerer male mice. Physiol. Behav., 61 (1997) 209±213. [3] Duchamp-Viret, P., Duchamp, A. and Chaput, M., GABAergic control of odor-induced activity in the frog olfactory bulb: electrophysiological study with picrotoxin and bicuculline. Neuroscience, 53 (1993) 111±120. [4] FeÂron, C. and Baudoin, C., Social isolation induces preference for odours of oestrous females in sexually naive male staggerer mutant mice. Chem. Senses, 23 (1998) 119±121. [5] Franklin, K.B.J. and Paxinos, G., The Mouse Brain in Stereotaxic Coordinates, Academic Press, New York, 1997. [6] Greer, C.A. and HalaÁsz, N., Plasticity of dendrodendritic microcircuits following mitral cell loss in the olfactory
[7] [8] [9] [10]
[11]
[12]
[13]
[14] [15] [16] [17]
[18] [19]
bulb of the murine mutant Purkinje cell degeneration. J. Comp. Neurol., 256 (1987) 284±298. Jiang, T. and Holley, A., Some properties of receptive ®elds of olfactory mitral/tufted cells in the frog. J. Neurophysiol., 68 (1992) 726±733. Kopala, L.C., Good, K.P., Koczapski, A.B. and Honer, W.G., Olfactory de®cits in patients with schizophrenia and severe polydipsia. Biol. Psychiatry, 43 (1998) 497±502. Landis, D.M. and Sidman, R.L., Electron microscopic analysis of postnatal histogenesis in the cerebellar cortex of staggerer mutant mice. J. Comp. Neurol., 179 (1978) 831±863. Matysiak Scholze, U. and Nehls, M., The structural integrity of ROR alpha isoforms is mutated in staggerer mice: cerebellar coexpression of ROR alpha1 and ROR alpha4. Genomics, 43 (1997) 78±84. Monnier, Z., Bahjaoui-Bouhaddi, M., Bride, J., Bride, M., Math, F. and Propper, A., Structural and immunohistological modi®cations in the olfactory bulb of the staggerer mutant mouse. Biol. Cell, 91 (1999) 29±44. Mouly, A.M., Elaagouby, A. and Ravel, N., A study of the effects of noradrenaline in the rat olfactory bulb using evoked ®eld potential response. Brain Res., 681 (1995) 47± 57. Nakagawa, S., Watanabe, M. and Inoue, Y., Altered gene expression of the N-Methyl-D-aspartate receptor channel subunits in Purkinje cells of the staggerer mutant mouse. Eur. J. Neurosciences, 8 (1996) 2644±2651. Nicoll, R.A. and Jahr, C.E., Self-excitation of olfactory bulb neurones. Nature, 296 (1982) 441±444. Nordin, S., Almkvist, O., Berglund, B. and Wahlund, L.O., Olfactory dysfunction for pyridine and dementia progression in Alzheimer disease. Arch. Neurol., 54 (1997) 993±998. Sidman, R., Lane, P. and Dickie, M., Staggerer: a new mutation in the mouse affecting cerebellum. Science, 137 (1962) 610±612. Steinmayr, M., AndreeÂ, E., Conquet, F., Rondi Reig, L., Delhaye-Bouchaud, N., Auclair, N., Daniel, H., CreeÂpel, F., Mariani, J., Sotelo, C. and Becker-AndreeÂ, M., Staggerer phenotype in retinoid-related orphan receptor alpha-de®cient mice. Proc. Natl. Acad. Sci. USA, 95 (1998) 3960± 3965. Yoon, C.H., Developmental mechanism for changes in cerebellum of staggerer mouse, a neurological mutant of genetic origin. Neurology, 22 (1972) 743±754. Zanjani, H.S., Herrup, K., Guastavino, J.M., DelhayeBouchaud, N. and Mariani, J., Developmental studies of the inferior olivary nucleus in staggerer mutant mice. Dev. Brain Res., 82 (1994) 18±28.