Expression of neurotrophin-3 in the mouse forebrain: Insights from a targetedLacZ reporter

Vigers, Alison J.; Baquet, Zachary C.; Jones, Kathryn

doi:10.1002/(sici)1096-9861(20000117)416:3<398::aid-cne10>3.0.co;2-p

Cited by 51 publications

(50 citation statements)

References 68 publications

(108 reference statements)

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“…27 In the forebrain and midbrain, the regional distribution pattern of lacZ expressing cells in morphine-treated animals (500 mg kg −1 per 60 h) appeared qualitatively normal and similar to the distribution pattern described previously for drug-free animals. 27 However, morphine-treated animals consistently showed much stronger lacZ reporter activity for the lateral septum and the CA2 region and the dentate gyrus of the hippocampus, in comparison to drug-free littermate controls (Figure 7a-d). The bed nucleus of the stria terminalis (BNST) contained, in areas of immediate vicinity to the lateral septum, a few scattered lacZ+ neurons in morphine-treated animals while drug-free animals had no lacZ reporter activity in that brain region (Figure 7e, f).…”

Section: Regional Distribution Pattern Of Nt-3 Expression Suggests Tasupporting

confidence: 81%

“…In order to learn more about the regional distribution and transcriptional regulation of NT-3 in opiate-exposed mice, we studied transgenic mice with a lacZ reporter coding sequence integrated into the endogenous NT-3 locus. 27 In the forebrain and midbrain, the regional distribution pattern of lacZ expressing cells in morphine-treated animals (500 mg kg −1 per 60 h) appeared qualitatively normal and similar to the distribution pattern described previously for drug-free animals. 27 However, morphine-treated animals consistently showed much stronger lacZ reporter activity for the lateral septum and the CA2 region and the dentate gyrus of the hippocampus, in comparison to drug-free littermate controls (Figure 7a-d).…”

Section: Regional Distribution Pattern Of Nt-3 Expression Suggests Tamentioning

confidence: 99%

“…27 However, NT-3 reporter gene expression was, both in newborn and adult brain, strikingly absent in catecholaminergic neurons of the entire hindbrain and pons, including A6 and A2 (Figure 7h). These results are consistent with data obtained from emulsion-dipped sections from wild-type pons hybridized with radiolabeled NT-3 antisense cRNA, showing no specific labeling over noradrenergic cells (Figure 1d).…”

Section: Regional Distribution Pattern Of Nt-3 Expression Suggests Tamentioning

confidence: 99%

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Neurotrophin-3 modulates noradrenergic neuron function and opiate withdrawal

et al. 2001

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Ongoing drug use in an opiate-addicted individual could be reinforced by withdrawal reactions that occur when drug use is halted abruptly. 1 Overactivity and disinhibition of brainstem noradrenergic neurons is thought to be a key mechanism for the hyperautonomic state and for many of the somatic symptoms that occur during acute withdrawal 2 and also for the acquisition of avoidance behaviors after occurrence of withdrawal reactions. 3 Little is known about endogenous factors that regulate noradrenergic neuron function and opiate withdrawal-related behaviors. Molecules of the nerve growth factor family may influence neuronal health and plasticity both in the developing and in the adult brain, including the reward and addiction circuitry. 4 Brainstem noradrenergic neurons of the adult rodent and primate brain express the neurotrophin-3 (NT-3) high affinity receptor, TrkC, 5-7 as well as the brain derived neurotrophic factor (BDNF) and neurotrophin-4/5 (NT-4/5) receptor TrkB. In selected neuronal populations, NT-3 may promote growth and survival by binding to TrkB or TrkA, the high affinitity receptor for nerve growth factor (NGF). [8][9][10] Although levels of NT-3 and TrkC mRNA are altered in several brain areas during opiate withdrawal, 5 in vivo evidence of a role for NT-3 in opiate withdrawal and noradrenergic neuron function is still lacking. The perinatal lethality of conventional NT-3 knock-out mice, 11,12 due to major cardiovascular malformations, 13 prevented the use of these mice to study NT-3 in the adult brain. Using a conditional knock-out strategy with Cre/loxP mediated NT-3 gene deletion that results in complete loss of NT-3 in the central nervous system in mice with normal viability, fertility and lifespan, 14 we show here for the first time that NT-3 modulates electrophysiological responses and neurochemistry of brainstem noradrenergic neurons and that NT-3 is essential both for opiate withdrawal-induced avoidance behavior and for the somatic symptoms that occur during acute withdrawal. NT-3 modulates expression of tyrosine hydroxylase but is not essential for survival of noradrenergic neuronsWe used two transgenic lines, a conditional NT3 mutant 14 and a transgenic line carrying an NT3 transgene under the control of the DBH promoter to examine the consequences of NT3 deficiency as well as NT3 overexpression in opiate withdrawal reactions and in noradrenergic neuron function in vivo. Expression of the recombinase cre under control of the nestin promoter results in complete deletion of NT-3 during prenatal development of the brain and spinal cord. 14 To ascertain ubiquitous nestin-cre expression, a reporter line that expressed beta-galactosidase in all tissues upon cre-mediated removal of a stop translation sequence 15 was crossed with the nestin-cre transgenic line. The results shown in Figure 1a-c indicate that cre-mediated recombination is complete throughout the brain, consistent with previous Northern blot results. 14 In adult brain, NT-3 has been implicated in survival of noradrenergic neuron...

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Section: Regional Distribution Pattern Of Nt-3 Expression Suggests Tasupporting

confidence: 81%

Section: Regional Distribution Pattern Of Nt-3 Expression Suggests Tamentioning

confidence: 99%

Section: Regional Distribution Pattern Of Nt-3 Expression Suggests Tamentioning

confidence: 99%

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Neurotrophin-3 modulates noradrenergic neuron function and opiate withdrawal

et al. 2001

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“…19 Its cognate receptor, TrkC, is expressed most prominently in hippocampal dentate granule cells. 20 Haploinsufficiency in the TrkC gene causes structural alterations specifically in the dentate gyrus, but not in CA1 or CA3 subregions.…”

Section: Discussionmentioning

confidence: 99%

Reduced expression of the Sp4 gene in mice causes deficits in sensorimotor gating and memory associated with hippocampal vacuolization

et al. 2004

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Hf-1b/Sp4, a member of the Sp1 family of transcription factors, is expressed restrictively in the developing nervous system and most abundantly in adult hippocampus in mice. Here, we report the generation of hypomorphic Sp4 allele mice, in which the Sp4 deficiency can be rescued by the expression of Cre recombinase. Vacuolization was detected in the hippocampal gray matter of the mutant Sp4-deficient mice. Expression analysis of Sp4 mutant hippocampi revealed an age-dependent decrease in neurotrophin-3 expression in the dentate granule cells. Hypomorphic Sp4 mutant mice displayed robust deficits in both sensorimotor gating and contextual memory. The restoration of Sp4 expression, via a Cre-dependent rescue strategy, completely rescued all the observed molecular, histological and behavioral abnormalities. Our studies thus reveal a novel Sp4 pathway that is essential for hippocampal integrity and modulates behavioral processes relevant to psychiatric disorders. Molecular Psychiatry ( Keywords: transcription factor; hippocampus; schizophrenia; mouse model; behavior; Cre recombinase; genetic rescue Sp1, the prototypal member of the Sp family of transcription factors, has been demonstrated to be essential for embryogenesis. 1 The reduction of its expression in heterozygous Sp1 mice causes a decreased expression of its downstream target gene, MeCP2, whose mutation is responsible for Rett syndrome, a human neurodevelopmental disorder. 2 Recently, Sp1 and other glutamine-rich transcription factors have been implicated in the pathogenesis of neurodegenerative diseases. 3,4 Sp4, also known as HF1b, is another member of the Sp1 family of transcription factors. Sp1 and Sp4 proteins have approximately 50% homology in primary structure, which consists of two glutamine-rich transcription activation domains and Cterminal three zinc-finger DNA binding domains. 5 Both proteins recognize the same DNA binding motif with similar affinity, and often functionally substitute for each other in vitro. 6 Previously, we found that HF-1b/ Sp4 null mutant mice suffer from cardiac arrhythmia and sudden death. 7 Although Sp4 has some role in heart development, it is expressed predominantly in the developing nervous system. 8,9 As yet, the specific role of Sp4 in the nervous system remains to be determined.In our endeavor to understand the function of HF-1b/Sp4 in the nervous system, we have undertaken a genetic rescue strategy to generate hypomorphic Sp4 alleles. Targeted transgenes were designed to enable the restoration of the expression of the Sp4 gene in the context of its endogenous locus in order to rescue any abnormal in vivo phenotypes. The generated hypomorphic Sp4 allele mice were grossly normal and displayed no increased lethality. Unexpectedly, the mutant mice displayed both vacuolization in the hippocampus and abnormal behavioral phenotypes, particularly with regard to contextual memory and sensorimotor gating deficits. Hence, these studies suggest a new molecular pathway involving the Sp4 gene that functions within the hippocampu...

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“…BDNF is highly expressed in the cortex, hippocampus, limbic structures, cerebellum, and the olfactory bulb (Huang and Reichardt, 2001;Vigers et al, 2000;Yan et al, 1997), where it is involved in basic neuronal functions, such as cell survival, axonal outgrowth, dendritic growth, and synaptic plasticity. Animal studies also support the association between BDNF and several treatments for mood disorders, including antidepressants, lithium, valproate, electroconvulsive therapy, and repetitive transcranial magnetic stimulation.…”

Section: Introductionmentioning

confidence: 99%

Neuronal Correlates of Brain-derived Neurotrophic Factor Val66Met Polymorphism and Morphometric Abnormalities in Bipolar Disorder

Matsuo

Walss‐Bass

Nery

et al. 2009

Neuropsychopharmacol

112

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The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has been proposed as a possible candidate for involvement in the pathophysiology of bipolar disorder (BD). To determine whether an association exists between the BDNF Val66Met genotype and morphometric abnormalities of the brain regions involved in memory and learning in BD and healthy subjects. Forty-two BD patients and 42 healthy subjects were studied. Interactions between BDNF Val66Met genotype and diagnosis in gray (GM) volumes were analyzed using an optimized voxel-based morphometry technique. Declarative memory function was assessed with the California Verbal Learning Test II. Left and right anterior cingulate GM volumes showed a significant interaction between genotype and diagnosis such that anterior cingulate GM volumes were significantly smaller in the Val/Met BD patients compared with the Val/Val BD patients (left P ¼ 0.01, right P ¼ 0.01). Within-group comparisons revealed that the Val/Met carriers showed smaller GM volumes of the dorsolateral prefrontal cortex compared with the Val/Val subjects within the BD patient (P ¼ 0.01) and healthy groups (left P ¼ 0.03, right P ¼ 0.03). The Val/ Met healthy subjects had smaller GM volumes of the left hippocampus compared with the Val/Val healthy subjects (Po0.01). There was a significant main effect of diagnosis on memory function (P ¼ 0.04), but no interaction between diagnosis and genotype was found (P ¼ 0.48). The findings support an association between the BDNF Val66Met genotype and differential gray matter content in brain structures, and suggest that the variation in this gene may play a more prominent role in brain structure differences in subjects affected with BD.

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Expression of neurotrophin-3 in the mouse forebrain: Insights from a targetedLacZ reporter

Cited by 51 publications

References 68 publications

Neurotrophin-3 modulates noradrenergic neuron function and opiate withdrawal

Neurotrophin-3 modulates noradrenergic neuron function and opiate withdrawal

Reduced expression of the Sp4 gene in mice causes deficits in sensorimotor gating and memory associated with hippocampal vacuolization

Neuronal Correlates of Brain-derived Neurotrophic Factor Val66Met Polymorphism and Morphometric Abnormalities in Bipolar Disorder

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