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Pharmacological and Developmental Aspects on Neuronal Plasticity
Linköping University, Department of Clinical and Experimental Medicine, Geriatric . Linköping University, Faculty of Health Sciences.
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Neuronal plasticity means the ability of the brain, its cells and networks to adapt and adjust to new challenges, a process which is ongoing throughout life. The goal of this thesis was to gain better understanding of the molecular events that follow different types of stimulations of brain structures such as the hippocampus, a key region for cognitive functions with overriding control on the corticosteroid system. A better knowledge of the mechanisms involved in neuronal plasticity is fundamental in the development of strategies for improving health in patients suffering from major depression or cognitive disorders such as Alzheimer’s disease.

Antidepressant drugs induce the expression of several genes involved in neuronal plasticity, a mechanism which may explain the several weeks time lag between treatment initiation and clinical effect commonly observed in patients. Besides, there are indications that disturbances in the corticosteroid system are involved in the pathogenesis of major depression. Therefore, the mRNA expression of the glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) as well as of the immediate-early genes NGFI-A and NGFI-B was analyzed using in situ hybridization in the hippocampus and cortex after 21 days treatment with various antidepressant drugs having different monoaminergic profiles. The mRNA expression of the transcription factors was selectively increased depending on region and also on the monoaminergic profile of the drug given. Generally, drugs with less specificity for monoamines had an overall more anatomically wide-spread inducible effect.

In a follow-up study the message expression of the synaptic protein NP2 was investigated in a similar setting where long-term (21 days) was compared with short-term (3 days) antidepressant treatment. In addition to the hippocampus, the medial habenula, a relay station within the limbic system was analyzed. Overall there was an upregulation of NP2 mRNA expression following long-term treatment irrespective of the monoaminergic profile of the drug. Simultaneously, NP2 mRNA was analyzed in rats exposed to enriched, normal or deprived environments respectively, an experimental setting known to affect neuronal plasticity. However, in contrast to the pharmacological treatment, this environmental stimulation did not lead to alterations in NP2 mRNA expression in any of the regions studied.

Finally, the function of NP2 as well as the closely related proteins NP1 and NPR was investigated. The “knock-out mouse” technique was used to eliminate these neuronal pentraxins (NPs), both individually and in various combinations. Since previous data had suggested that the NPs are involved in synaptic development, axonal refinement in the visual system during development was analyzed in these animals. In the NP1/NP2 knock-out mice, synaptic formation, axonal development and refinement occurred at a significantly slower rate than in wild-type mice, indicating that the NPs may be necessary for activity-dependent synaptogenesis.

In conclusion, the results of the studies constituting this thesis demonstrate that long-term treatment with antidepressant drugs, possessing different monoaminergic profiles, has selective effects on the expression of NGFI-A, NGFI-B, GR and MR in the mammalian brain. In general, the least selective drugs exhibit the most profound effect suggesting that induction of neuronal plasticity is more effective with multiple neuronal inputs. The results also show that NP2 expression is induced by antidepressant drugs, in contrast to environmental stimulation, supporting the presence of different pathways for inducing neuronal plasticity depending on type of stimuli. Finally, this thesis indicates that the neuronal pentraxins play an important part in synaptic development.

 

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2009. , 62 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1151
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-51450ISBN: 978-91-7393-519-7 (print)OAI: oai:DiVA.org:liu-51450DiVA: diva2:274990
Public defence
2009-12-18, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings Universitet, Linköping, 00:00 (Swedish)
Opponent
Supervisors
Available from: 2009-11-02 Created: 2009-11-02 Last updated: 2009-11-02Bibliographically approved
List of papers
1. Chronic amitriptyline treatment induces hippocampal NGFI-A, glucocorticoid receptor and mineralocorticoid receptor mRNA expression in rats
Open this publication in new window or tab >>Chronic amitriptyline treatment induces hippocampal NGFI-A, glucocorticoid receptor and mineralocorticoid receptor mRNA expression in rats
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1998 (English)In: Brain Research. Molecular Brain Research, ISSN 0169-328X, E-ISSN 1872-6941, Vol. 62, no 1, 92-95 p.Article in journal (Refereed) Published
Abstract [en]

Adult male rats were treated with the antidepressant drug amitriptyline for 21 days and the expression of specific transcription factors was examined. NGFI-A mRNA expression was increased in the hippocampus and in the cerebral cortex. MR mRNA was increased in the hippocampus while GR mRNA was increased in selective hippocampal regions. There was no change in the NGFI-B mRNA expression. Thus, NGFI-A may be a mediator of plasticity-related phenomena induced by antidepressant drugs.

Place, publisher, year, edition, pages
Elsevier Science B.V., 1998
Keyword
NGFI-A, glucocorticoid receptor, antidepressant, hippocampus, transcription factor
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-51403 (URN)10.1016/S0169-328X(98)00243-5 (DOI)
Available from: 2009-10-30 Created: 2009-10-30 Last updated: 2017-12-12Bibliographically approved
2. Selective effects on NGFI-A, MR, GR and NGFI-B hippocampal mRNA expression after chronic treatment with different subclasses of antidepressants in the rat
Open this publication in new window or tab >>Selective effects on NGFI-A, MR, GR and NGFI-B hippocampal mRNA expression after chronic treatment with different subclasses of antidepressants in the rat
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2000 (English)In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 151, no 1, 7-12 p.Article in journal (Refereed) Published
Abstract [en]

There is a latency period of several weeks before the onset of clinical effect of antidepressant drugs. The detailed mechanisms underlying drug-induced adaptive neuronal changes are not known. To elucidate the involvement of changes in gene expression of candidate transcription factors, we treated rats for 21 days with buspirone, fluoxetine, 8-OH-DPAT and moclobemide. In situ hybridization was used to study mRNAs encoding NGFI-A, NGFI-B and the glucocorticoid receptors, MR and GR. NGFI-A mRNA expression increased profoundly in the hippocampal formation and the cerebral cortex after all drug treatments, especially after moclobemide treatment (77-122% increase), with the exception of buspirone. MR mRNA expression was induced in hippocampal CA1/CA2 subregions (27-37%) by all antidepressants, while moclobemide and 8-OH-DPAT significantly increased GR gene expression mainly in the CA1 region (31-44%). NGFI-B mRNA was significantly decreased in the hippocampal CA3 subfield (23%) and restrosplenial granular cortex (38%) by moclobemide treatment. There are selective effects of antidepressant drugs on specific transcription factors. These may be important for adaptive neuronal and neuroendocrine changes after antidepressant treatment including HPA axis negative feedback regulation.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-27674 (URN)10.1007/s002130000468 (DOI)12412 (Local ID)12412 (Archive number)12412 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
3. Neuronal pentraxins mediate synaptic refinement in the developing visual system
Open this publication in new window or tab >>Neuronal pentraxins mediate synaptic refinement in the developing visual system
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2006 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 26, no 23, 6269-6281 p.Article in journal (Refereed) Published
Abstract [en]

Neuronal pentraxins (NPs) define a family of proteins that are homologous to C-reactive and acute-phase proteins in the immune system and have been hypothesized to be involved in activity-dependent synaptic plasticity. To investigate the role of NPs in vivo, we generated mice that lack one, two, or all three NPs. NP1/2 knock-out mice exhibited defects in the segregation of eye-specific retinal ganglion cell (RGC) projections to the dorsal lateral geniculate nucleus, a process that involves activity-dependent synapse formation and elimination. Retinas from mice lacking NP1 and NP2 had cholinergically driven waves of activity that occurred at a frequency similar to that of wild-type mice, but several other parameters of retinal activity were altered. RGCs cultured from these mice exhibited a significant delay in functional maturation of glutamatergic synapses. Other developmental processes, such as pathfinding of RGCs at the optic chiasm and hippocampal long-term potentiation and long-term depression, appeared normal in NP-deficient mice. These data indicate that NPs are necessary for early synaptic refinements in the mammalian retina and dorsal lateral geniculate nucleus. We speculate that NPs exert their effects through mechanisms that parallel the known role of short pentraxins outside the CNS.

Keyword
retinogeniculate, neuronal pentraxins, synaptic plasticity, LTP, long-term potentiation, LTD, long-term depression, development, knock-out, retinal ganglion cell
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-51407 (URN)10.1523/JNEUROSCI.4212-05.2006 (DOI)
Available from: 2009-10-30 Created: 2009-10-30 Last updated: 2017-12-12Bibliographically approved
4. Long-term treatment with antidepressants, but not environmental stimulation, induces expression of NP2 mRNA in hippocampus and medial habenula
Open this publication in new window or tab >>Long-term treatment with antidepressants, but not environmental stimulation, induces expression of NP2 mRNA in hippocampus and medial habenula
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2010 (English)In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1328, 24-33 p.Article in journal (Refereed) Published
Abstract [en]

Neuronal Pentraxin 2 (NP2, Narp), known to mediate clustering of glutamatergic AMPA receptors at synapses, is involved in activity-dependent synaptogenesis and synaptic plasticity. In experimental settings, antidepressant treatment as well as a stimulating environment has a positive influence on cognition and hippocampal plasticity. This study demonstrates that NP2 mRNA is robustly expressed in the hippocampus and the medial habenula (MHb), both regions implicated in cognitive functions. Furthermore, NP2 mRNA expression is enhanced in the hippocampal subregions as well as in the MHb after long-term treatment with antidepressant drugs of various monoaminergic profiles, indicating a common mode of action of different antidepressant drugs. This effect occurs at the time frame where clinical response is normally achieved. In contrast, neither environmental enrichment nor deprivation has any influence on long-term NP2 mRNA expression. These findings support an involvement of NP2 in the pathway of antidepressant induced plasticity, but not EE induced plasticity; that NP2 might constitute a common link for the action of different types of antidepressant drugs and that the MHb could be a putative region for further studies of NP2.

Place, publisher, year, edition, pages
Elsevier, 2010
Keyword
Neuronal pentraxins, narp, habenula, hippocampus, synaptic plasticity, antidepressant
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-51408 (URN)10.1016/j.brainres.2010.03.004 (DOI)000277682400003 ()
Note
On the day of the defence day the status of this article was: Submitted.Available from: 2009-10-30 Created: 2009-10-30 Last updated: 2017-12-12Bibliographically approved

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