GRK5过表达对P301S Tau转基因小鼠抑郁样行为的影响及其机制

doi:10.13481/j.1671-587X.20230304

Abstract

Abstract:

Objective To discuss the effect of G protein-coupled receptor kinase5（GRK5） over-expression on the depression-like behaviors of the P301S Tau transgenic mice，and to clarify its possible mechanism. Methods Seventeen male P301S Tau mice were randomly divided into blank control group （given no treatment） and negative control group （given negative control virus in bilateral hippocampus regions），over-expression group （given GRK5 over-expression virus in bilateral hippocampus regions）. The sugar-water preference test was used to detect the sugar-water preference rates of the mice in various groups， the percentages of immobility time of the mice in various groups were detected by tail suspension test（TST） and forced swimming test（FST）； the expression levels of neurological function-related proteins in hippocampus tissue of the mice in various groups were dectated by Western blotting method； the expressions of microglia marker protein （IBA1）， neuronal marker protein （NeuN）， and astrocyte marker protein （GFAP） in hippocampus tissue of the mice in various groups were detected by immunofluorescence staining. Result The sugar-water preference assay results showed that compared with blank control and negative control groups， the percentage of sugar-water preference of the mice in over-expression group was decreased（P<0.05）. The TST and FST results showed that the percentages of immobility time of the mice in over-expression group were increased compared with blank control and negative control groups （P<0.05）. The Western blotting results showed that the expression levels of GRK5， Tau T205， and IBA1 proteins in hippocampus tissue of the mice in over-expression group were increased （P<0.05） and the expression level of synatotagmin（SYN） protein was decreased （P<0.05）.The immunofluorescence staining results showed that compared with blank control group， the fluorescence expression of enhanced green fluoorescence protein（EGFP） in hippocampus tissue of the mice in negative control and over-expression groups could be seen and the EGFP was mainly co-localized with the NeuN； EGFP was hardly found in the microglia and astrocytes；compared with blank control and negative control groups， the number of microglia in hippocampus tissue of the mice in over-expression group was increased（P<0.05）. Conclusion Over-expression of GRK5 in hippocampus tissue of the P301S Tau mice induces the depressive-like behaviors，and its mechanism may be related to the increasing of the expression of GRK5 in nucleus of the neurons.

Key words: Mice， P301S, G protein-coupled receptor kinase 5, Depression-like behavior, Tau protein

CLC Number:

R749.4

Tianzhen ZHANG,Hongtao SHEN,Zheng GONG,Bin ZHAO,Yan WANG. Effect of GRK5 over-expression on depression- like behavior in P301S Tau transgenic mice and its mechanism[J].Journal of Jilin University(Medicine Edition), 2023, 49(3): 573-579.

Figures/Tables 6

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References 25

1	KOMOLOV K E， SULON S M， BHARDWAJ A，et al. Structure of a GRK5-calmodulin complex reveals molecular mechanism of GRK activation and substrate targeting［J］. Mol Cell， 2021， 81（2）： 323-339.
2	GUO J J， YANG X H， WESTON D J， et al. Abscisic acid receptors： past， present and future［J］. J Integr Plant Biol， 2011， 53（6）： 469-479.
3	BABA M， NAKAJO S， TU P H， et al. Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson’s disease and dementia with Lewy bodies［J］. Am J Pathol， 1998， 152（4）： 879-884.
4	ARAWAKA S， WADA M， GOTO S， et al. The role of G-protein-coupled receptor kinase 5 in pathogenesis of sporadic Parkinson’s disease［J］.J Neurosci，2006，26（36）： 9227-9238.
5	NIU B， LIU P P， SHEN M J， et al. GRK5 regulates social behavior via suppression of mTORC1 signaling in medial prefrontal cortex［J］. Cereb Cortex，2018，28（2）： 421-432.
6	WANG S C， CHUNG R H， KUO H W， et al. GRK5 is associated with the regulation of methadone dosage in heroin dependence［J］. Int J Neuropsychopharmacol， 2018， 21（10）： 910-917.
7	FRANKLIN J M， CARRASCO G A. G-protein receptor kinase 5 regulates the cannabinoid receptor 2-induced up-regulation of serotonin 2A receptors［J］. J Biol Chem， 2013， 288（22）： 15712-15724.
8	BYCHKOV E R， GUREVICH V V， JOYCE J N，et al. Arrestins and two receptor kinases are upregulated in Parkinson’s disease with dementia［J］. Neurobiol Aging， 2008， 29（3）： 379-396.
9	BARTHET G， CARRAT G， CASSIER E， et al. Beta-arrestin1 phosphorylation by GRK5 regulates G protein-independent 5-HT4 receptor signalling［J］. EMBO J， 2009， 28（18）： 2706-2718.
10	FERNÁNDEZ-RUIZ I. GRK5 linked to cardiac dysfunction and leukocyte recruitment after MI［J］. Nat Rev Cardiol， 2021， 18（5）： 308.
11	LIU L Y， LV J， LIN Z Q， et al. Co-overexpression of GRK5/ACTC1 correlates with the clinical parameters and poor prognosis of epithelial ovarian cancer［J］. Front Mol Biosci， 2021， 8： 785922.
12	JIANG L P， FAN S Q， XIONG Q X， et al. GRK5 functions as an oncogenic factor in non-small-cell lung cancer［J］. Cell Death Dis， 2018， 9（3）： 295.
13	YE J， WEN Y， SUN X F， et al. Socioeconomic deprivation index is associated with psychiatric disorders： an observational and genome-wide gene-by-environment interaction analysis in the UK biobank cohort［J］. Biol Psychiatry， 2021， 89（9）： 888-895.
14	COLIN M， DUJARDIN S， SCHRAEN-MASCHKE S， et al. From the prion-like propagation hypothesis to therapeutic strategies of anti-tau immunotherapy［J］. Acta Neuropathol， 2020， 139（1）： 3-25.
15	MORIGUCHI S， TAKAHATA K， SHIMADA H，et al.Excess tau PET ligand retention in elderly patients with major depressive disorder［J］.Mol Psychiatry，2021，26（10）： 5856-5863.
16	TAKEUCHI H， IBA M， INOUE H， et al. P301S mutant human tau transgenic mice manifest early symptoms of human tauopathies with dementia and altered sensorimotor gating［J］. PLoS One， 2011，6（6）： e21050.
17	SUN Y， GUO Y Q， FENG X J， et al. The behavioural and neuropathologic sexual dimorphism and absence of MIP-3α in tau P301S mouse model of Alzheimer’s disease［J］. J Neuroinflammation， 2020， 17（1）： 72.
18	YOSHIYAMA Y， HIGUCHI M， ZHANG B， et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model［J］. Neuron， 2007， 53（3）： 337-351.
19	奚耕思，张武会. 抑郁症发生机制研究进展［J］. 陕西师范大学学报（自然科学版）， 2011， 39（6）： 64-71.
20	王睿，黄树明. 抑郁症发病机制研究进展［J］. 医学研究生学报， 2014， 27（12）： 1332-1336.
21	MALHI G S， MANN J J. Depression［J］. Lancet， 2018， 392（10161）： 2299-2312.
22	刘聪，韩金红，王长虹. 海马神经元突触可塑性在抑郁症发病机制中的研究［J］. 中华行为医学与脑科学杂志， 2015， 24（5）： 423-426.
25	FALDINI E， AHMED T， BUEÉ L， et al. Tau- but not Aß-pathology enhances NMDAR-dependent depotentiation in AD-mouse models［J］. Acta Neuropathol Commun， 2019， 7（1）： 202.
24	MARZANO F， RAPACCIUOLO A， FERRARA N， et al. Targeting GRK5 for treating chronic degenerative diseases［J］. Int J Mol Sci， 2021， 22（4）： 1920.
25	HULLMANN J E， GRISANTI L A， MAKAREWICH C A， et al. GRK5-mediated exacerbation of pathological cardiac hypertrophy involves facilitation of nuclear NFAT activity［J］. Circ Res， 2014， 115（12）： 976-985.

Group	n	Sugar-water perference rate	Percentage of immobility time in FST	Percentage of immobility time in TST
Blank control	6	43.40±19.88	13.65±11.77	14.70±13.46
Negative control	5	38.56±13.21	15.46±3.85	12.64±6.07
Over-expression	5	78.65±5.47^*Δ	46.46±16.83^*Δ	44.03±16.17^*Δ

Group	GRK5	Tau T205	IBA1	GFAP	NeuN	PSD95	SYN
Blank control	0.98±0.02	1.08±0.10	1.07±0.13	1.05±0.05	0.85±0.22	1.02±0.03	1.05±0.07
Negative control	1.25±0.30	1.24±0.04	1.29±0.12	1.14±0.08	0.69±0.09	1.12±0.09	1.05±0.08
Over-expression	2.56±0.14^*Δ	1.54±0.11^*Δ	2.03±0.27^*Δ	1.05±0.10	0.57±0.13	1.06±0.10	0.74±0.10^*Δ

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Effect of GRK5 over-expression on depression- like behavior in P301S Tau transgenic mice and its mechanism

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