Altered Neurogranin Phosphorylation and Protein Levels Are Associated with Anxiety- and Depression-Like Behaviors in Rats Following Forced Swim Stress

Abstract

Here we tested the hypothesis that stress-induced alterations in Neurogranin (Ng) synthesis and/ or utilization might underlie stress-related depression and anxiety. Rats were randomly divided into five conditions: chronic swim stress (CS), acute swim stress (AS), and three control groups. The CS group was exposed to daily swim stress (5 min/day) for 14 consecutive days, the AS group received a single swim stress, and control groups were maintained in a stress-free condition. Both before and after swim stress, rats were tested for body weight gain, open-field locomotor activity, and saccharine preference. Ng and phospho-Ng (P-Ng) levels in the hippocampus and prefrontal cortex were determined by Western blot analysis. Compared to controls, CS animals displayed significantly decreased body weight gain, ambulation, and saccharine intake, and increased grooming behavior. CS animals had decreased Ng levels in the hippocampus and prefrontal cortex. In CS animals, Ng levels were positively correlated with saccharine intake and ambulation, and inversely correlated with grooming behavior. Compared to controls, AS increased immobility behavior and P-Ng and Ng levels in the hippocampus and prefrontal cortex. In AS animals, immobility behavior was positively correlated with the P-Ng in the prefrontal cortex. Thus, CS and AS produced opposing effects on Ng and P-Ng levels in the hippocampus and prefrontal cortex. Low Ng levels in the hippocampus were associated with anhedonic behavior in CS animals, whereas high P-Ng levels in the prefrontal cortex were associated with anxiety-like behavior in AS animals. Thus, Ng dysfunction might contribute to the neural mechanisms underlying stress-induced depression and anxiety.

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Li, H. , Lin, W. , Li, J. and Wang, W. (2014) Altered Neurogranin Phosphorylation and Protein Levels Are Associated with Anxiety- and Depression-Like Behaviors in Rats Following Forced Swim Stress. Journal of Behavioral and Brain Science, 4, 506-522. doi: 10.4236/jbbs.2014.411050.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] Blanchard, R.J., Mckittrick, C.R. and Blanchard, D.C. (2001) Animal Models of Social Stress: Effects on Behavior and Brain Neurochemical Systems. Physiology & Behavior, 73, 261-271.
http://dx.doi.org/10.1016/S0031-9384(01)00449-8
[2] Palanza, P. (2001) Animal Models of Anxiety and Depression: How Are Female Different? Neuroscience & Biobehavioral Reviews, 25, 219-223.
http://dx.doi.org/10.1016/S0149-7634(01)00010-0
[3] Matuzany-Ruban, A., Schreiber, G., Farkash, P. and Avissar, S. (2006) Phosducin-Like Protein Levels in Leukocytes of Patients with Major Depression and in Rat Cortex: The Effect of Chronic Treatment with Antidepressants. Psychiatry Research, 141, 287-294.
http://dx.doi.org/10.1016/j.psychres.2005.09.009
[4] Paul, S.M. (1988) Anxiety and Depression: A Common Neurobiological Substrate? The Journal of Clinical Psychiatry, 49, 13-16.
[5] Anand, K.J. and Scalzo, F.M. (2000) Can Adverse Neonatal Experiences Alter Brain Development and Subsequent Behavior? Biology of the Neonate, 77, 69-82.
http://dx.doi.org/10.1159/000014197
[6] Bremner, J.D. (2002) Structural Changes in the Brain in Depression and Relationship to Symptom Recurrence. CNS Spectrosc, 7, 135-139.
[7] McEwen, B.S. (2000) Effects of Adverse Experiences for Brain Structure and Function. Biological Psychiatry, 48, 721-731.
http://dx.doi.org/10.1016/S0006-3223(00)00964-1
[8] McEwen, B.S. (2001) Stress, Sex, Hippocampal Plasticity: Relevance to Psychiatric Disorders. Clinical Neuroscience Research, 1, 19-34.
http://dx.doi.org/10.1016/S1566-2772(00)00004-9
[9] Qi, X.L., Lin, W.J., Li, J.F., Pan, Y.Q. and Wang, W.W. (2006) The Depressive-Like Behaviors Are Correlated with Decreased Phosphorylation of Mitogen-Activated Protein Kinases in Rat Brain Following Chronic Forced Swim Stress. Behavioural Brain Research, 175, 233-240.
http://dx.doi.org/10.1016/j.bbr.2006.08.035
[10] Winder, D.G. and Schremm, N.L. (2001) Plasticity and Behavior: New Genetic Techniques to Address Multiple Forms and Functions. Physiology & Behavior, 73, 763-780.
http://dx.doi.org/10.1016/S0031-9384(01)00514-5
[11] Pasinelli, P., Ramakers, G.M.J., Urban, I.J.A., Hens, J.J.H., Oestreicher, A.B., de Graan, P.N.E. and Gispen, W.H. (1995) Long-Term Potentiation and Synaptic Protein Phosphorylation. Behavioural Brain Research, 66, 53-59.
http://dx.doi.org/10.1016/0166-4328(94)00124-X
[12] Filipovic, D., Gavrilovic, L., Dronjak, S. and Radojcic, M.B. (2005) Brain Glucocorticoid Receptor and Heat Shock Protein 70 Levels in Rats Exposed to Acute, Chronic or Combined Stress. Neuropsychobiology, 51, 107-114.
http://dx.doi.org/10.1159/000084168
[13] Gronli, J., Bramham, C., Murison, R., Kanhema, T., Fiske, E., Bjorvatn, B., Ursin, R. and Portas, C.M. (2006) Chronic Mild Stress Inhibits BDNF Protein Expression and CREB Activation in the Dentate Gyrus but Not in the Hippocampus Proper. Pharmacology Biochemistry and Behavior, 85, 842-849.
http://dx.doi.org/10.1016/j.pbb.2006.11.021
[14] Mengesdorf, T., Proud, C.G., Mies, G. and Paschen, W. (2002) Mechanisms Underlying Suppression of Protein Synthesis Induced by Transient Focal Cerebral Ischemia in Mouse Brain. Experimental Neurology, 177, 538-546.
http://dx.doi.org/10.1006/exnr.2002.8002
[15] Pae, C.U., Mandelli, L., Serretti, A., Patkar, A.A., Kim, J.J., Lee, C.U., Lee, S.J., Lee, C., Ronchi, D.D. and Paik, I.H. (2007) Heat-Shock Protein-70 Genes and Response to Antidepressants in Major Depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 31, 1006-1011.
http://dx.doi.org/10.1016/j.pnpbp.2007.02.011
[16] Bilang-Bleue, A., Rech, J., De Carli, S., Holsboer, F. and Reul, J.M. (2002) Forced Swimming Evokes a Biphasic Response in CREB Phosphorylation in Extrahypothalamic Limbic and Neocortical Brain Structure in the Rat. European Journal of Neuroscience, 15, 1048-1060.
http://dx.doi.org/10.1046/j.1460-9568.2002.01934.x
[17] Houben, M.P., Lankhorst, A.J., van Dalen, J.J., Veldman, H., Joosten, E.A., Hamers, F.P., Gispen, W.H. and Schrama, L.H. (2000) Pre- and Postsynaptic Localization of RC3/Neurogranin in the Adult Rat Spinal: An Immunohistochemical Study. Journal of Neuroscience Research, 59, 750-759.
http://dx.doi.org/10.1002/(SICI)1097-4547(20000315)59:6<750::AID-JNR7>3.0.CO;2-B
[18] Watson, J.B., Sutcliffe, J.G. and Fisher, R.S. (1992) Localization of the Protein Kinase C Phosphorylation/Calmodulin-Binding Substrate RC3 in Dendritic Spines of Neostriatal Neurons. Proceedings of the National Academy of Sciences of the United States of America, 89, 8581-8585.
http://dx.doi.org/10.1073/pnas.89.18.8581
[19] Huang, K.P., Freesia, L., Li, J.F., Schuck, P. and McPhie, P. (2000) Calcium-Sensitive Interaction between Calmodulin and Modified Forms of Rat Brain Neurogranin/RC3. Biochemistry, 39, 7291-7299.
http://dx.doi.org/10.1021/bi000336l
[20] Pak, J.H., Huang, F.L., Li, J., Balschun, D., Reymann, K.G., Chiang, C., Westphal, H. and Huang, K.P. (2000) Involvement of Neurogranin in the Modulation of Calcium/Calmodulin-Dependent Protein Kinase II, Synaptic Plasticity, and Spatial Learning: A Study with Knockout Mice. Proceedings of the National Academy of Sciences of the United States of America, 97, 11232-11237.
http://dx.doi.org/10.1073/pnas.210184697
[21] Chakravarthy, B., Morley, P. and Whitfield, J. (1999) Ca2+-Calmodulin and Protein Kinase Cs: A Hypothetical Synthesis of Their Conflicting Convergences on Shared Substrate Domains. Trends in Neurosciences, 22, 12-16.
http://dx.doi.org/10.1016/S0166-2236(98)01288-0
[22] Mattson, M.P., LaFerla, F., Chan, S.L., Leissring, M.A., Shepel, P.N. and Geiger, J.D. (2000) Calcium Signaling in the ER: Its Role in Neuronal Plasticity and Neurodegenerative Disorders. Trends in Neurosciences, 23, 222-229.
http://dx.doi.org/10.1016/S0166-2236(00)01548-4
[23] Wang, H., Hu, Y. and Tsien, J.Z. (2006) Molecular and Systems Mechanisms of Memory Consolidation and Storage. Progress in Neurobiology, 79, 123-135.
http://dx.doi.org/10.1016/j.pneurobio.2006.06.004
[24] Fedorov, N.B., Pasinelli, P., Oestreicher, A.B., DeGraan, P.N. and Reymann, K.G. (1995) Antibodies to Postsynaptic PKC Substrate Neurogranin Prevent Long-Term Potentiation in Hippocampal CA1 Neurons. European Journal of Neuroscience, 7, 819-822.
http://dx.doi.org/10.1111/j.1460-9568.1995.tb00685.x
[25] Chang, J.W., Schumacher, E., Coulter, P.M., Vinters, H.V. and Watson, J.B. (1997) Dendritic Translocation of RC3/Neurogranin mRNA in Normal Aging, Alzheimer Disease and Fronto-Temporal Dementia. Journal of Neuropathology & Experimental Neurology, 56, 1105-1118.
http://dx.doi.org/10.1097/00005072-199710000-00004
[26] Miyakawa, T., Yared, E., Pak, J.H., Huang, F.L., Huang, K.P. and Crawley, J.N. (2001) Neurogranin Null Mutant Mice Display Performance Deficits on Spatial Learning Tasks with Anxiety Related Components. Hippocampus, 11, 763-775.
http://dx.doi.org/10.1002/hipo.1092
[27] Shukla, P.K., Tang, L. and Wang, Z.J. (2006) Phosphorylation of Neurogranin, Protein Kinase C, and Ca2+/Calmudulin Dependent Protein Kinase Ⅱ in Opioid Tolerance and Dependence. Neuroscience Letters, 404, 266-269.
[28] Ruano, D., Aulchenko, Y.S., Macedo, A., Soares, M.J., Valente, J., Azevedo, M.H., Hutz, M.H., Gama, C.S., Lobato, M.I., Belmontede-Abreu, P., Goodman, A.B., Pato, C., Heutink, P. and Palha, J.A. (2006) Association of the Gene Encoding Neurogranin with Schizophrenia in Males. Journal of Psychiatric Research, 42, 125-133.
[29] Wu, J., Li, J., Huang, K.P. and Huang, F.L. (2002) Attenuation of Protein Kinase C and cAMP-Dependent Protein Kinase Signal Transduction in the Neurogranin Knockout Mouse. Journal of Biological Chemistry, 277, 19498-19505.
http://dx.doi.org/10.1074/jbc.M109082200
[30] Neuner-Jehle, M., Rhyner, T.A. and Borbely, A.A. (1995) Sleep Deprivation Differentially Alters the mRNA and Protein Levels of Neurogranin in Rat Brain. Brain Research, 685, 143-153.
http://dx.doi.org/10.1016/0006-8993(95)00416-N
[31] Chen, C.C. (1994) Alterations of Protein Kinase C Isozyme and Substrate Proteins in Mouse Brain after Electroconvulsive Seizures. Brain Research, 648, 65-72.
http://dx.doi.org/10.1016/0006-8993(94)91906-2
[32] Li, H., Li, Q.H., Zhu, Z.L., Chen, R., Cheng, D.X., Cai, Q., Jia, N. and Song, L. (2007) Prenatal Restraint Stress Decreases Neurogranin Expression in Rat Offspring Hippocampus. Acta Physiologica Sinica, 59, 299-304. (In Chinese)
[33] Mizoguchi, K., Isgige, A., Aburada, M. and Tabira, T. (2003) Chronic Stress Attenuates Glucocorticoid Negative Feedback: Involvement of the Prefrontal Cortex and Hippocampus. Neuroscience, 119, 887-897.
http://dx.doi.org/10.1016/S0306-4522(03)00105-2
[34] Daenen, E.W., Van der Heyden, J.A., Kruse, C.G., Wolterink, G. and Van Ree, J.M. (2001) Adaptation and Habituation to an Open Field and Response to Various Stressful Events in Animals with Neonatal Lesions in the Amygdala or Ventral Hippocampus. Brain Research, 918, 153-165.
http://dx.doi.org/10.1016/S0006-8993(01)02987-0
[35] Vyas, A., Mitra, R., Shankaranarayana Rao, B.S. and Chattarji, S. (2002) Chronic Stress Induces Contrasting Patterns of Dendritic Remodeling in Hippocampal and Amygdaloid Neurons. Journal of Neuroscience, 22, 6810-6818.
[36] Coryell, W., Nopoulos, P., Drevets, W., Wilson, T. and Andreasen, N.C. (2005) Subgenual Prefrontal Cortex Volumes in Major Depressive Disorder and Schizophrenia: Diagnostic Specificity and Prognostic Implications. American Journal of Psychiatry, 162, 1706-1712.
http://dx.doi.org/10.1176/appi.ajp.162.9.1706
[37] Dal-Zotto, S., Marti, O. and Armario, A. (2000) Influence of Single or Repeated Experience of Rats with Forced Swimming on Behavioural and Physiological Responses to the Stressor. Behavioural Brain Research, 114, 175-181.
http://dx.doi.org/10.1016/S0166-4328(00)00220-5
[38] Blustein, J.E., Ciccolone, L. and Bersh, P.J. (1998) Evidence that Adaptation to Cold Water Swim-Induced Analgesia Is a Learned Response. Physiology & Behavior, 63, 147-150.
http://dx.doi.org/10.1016/S0031-9384(97)00382-X
[39] Paxinos, G. and Watson, C.R. (1998) The Rat Brain in Stereotaxic Coordinate. 4th Edition, Academic Press, New York.
[40] Ducottet, C. and Belzung, C. (2004) Behaviour in the Elevated Plus-Maze Predicts Coping after Subchronic Mild Stress in Mice. Physiology & Behavior, 81, 417-426.
http://dx.doi.org/10.1016/j.physbeh.2004.01.013
[41] Kalueff, A.V. and Tuohimaa, P. (2005) The Grooming Analysis Algorithm Discriminates between Different Levels of Anxiety in Rats: Potential Utility for Neurobehavioral Stress Research. Journal of Neuroscience Methods, 143, 169-177.
http://dx.doi.org/10.1016/j.jneumeth.2004.10.001
[42] Pijlman, F.T.A. and Van Ree, J.M. (2002) Physical but Not Emotional Stress Induces a Delay in Behavioural Coping Responses in Rats. Behavioural Brain Research, 136, 365-373.
http://dx.doi.org/10.1016/S0166-4328(02)00128-6
[43] Sareen, J., Cox, B.J., Stein, M.B., Afifi, T.O., Fleet, C. and Asmundson, G.J. (2007) Physical and Mental Comorbidity, Disability, and Suicidal Behavior Associated with Posttraumatic Stress Disorder in a Large Community Sample. Psychosomatic Medicine, 69, 242-248.
http://dx.doi.org/10.1097/PSY.0b013e31803146d8
[44] Shen, C.P., Tsimberg, Y., Salvadore, C. and Meller, E. (2004) Activation of Erk and JNK MAPK Pathways by Acute Swim Stress in Rat Brain Regions. BMC Neuroscience, 5, 36.
[45] Fuchs, E. and Flugge, G. (2003) Chronic Social Stress: Effects on Limbic Brain Structures. Physiology & Behavior, 79, 417-427.
http://dx.doi.org/10.1016/S0031-9384(03)00161-6
[46] Li, G.L., Farooque, M., Lewen, A., Lennmyr, F., Holtz, A. and Olsson, Y. (2000) MAP2 and Neurogranin as Markers for Dendritic Lesions in CNS Injury. An Immunohistochemical Study in the Rat. APMIS, 108, 98-106.
http://dx.doi.org/10.1034/j.1600-0463.2000.d01-32.x
[47] Aydemir, O., Deveci, A. and Taneli, F. (2005) The Effect of Chronic Antidepressant Treatment on Serum Brain-Derived Neurotrophic Factor Levels in Depressed Patients: A Preliminary Study. Progress in Neuro-Psycho-pharmacology and Biological Psychiatry, 29, 261-265.
http://dx.doi.org/10.1016/j.pnpbp.2004.11.009
[48] Itoh, T., Tokumura, M. and Abe, K. (2004) Effects of Rolipram, a Phosphodiesterase 4 Inhibitor, in Combination with Imipramine on Depressive Behavior, CRE-Binding Activity and BDNF Level in Learned Helplessness Rats. European Journal of Pharmacology, 498, 135-142.
http://dx.doi.org/10.1016/j.ejphar.2004.07.084
[49] Mons, N., Enderlin, V., Jaffard, R. and Higueret, P. (2001) Selective Age-Related Changes in the PKC-Sensitive, Calmodulin-Binding Protein, Neurogranin, in the Mouse Brain. Journal of Neurochemistry, 79, 859-867.
http://dx.doi.org/10.1046/j.1471-4159.2001.00646.x
[50] Bruijnzeel, A.W., Stam, R. and Wiegant, V.M. (2001) Effect of a Benzodiazepine Receptor Agonist and CRH Receptor Antagonist on Long-Term Foot Shock-Induced Increase in Defensive Withdrawal Behavior. Psychopharmacology, 158, 132-139.
http://dx.doi.org/10.1007/s002130100863
[51] Morrow, B.A., Elsworth, J.D. and Roth, R.H. (2002) Fear-Like Biochemical and Behavioral Responses in Rats to the Predator Odor, TMT, Are Dependent on the Exposure Environment. Synapse, 46, 11-18.
http://dx.doi.org/10.1002/syn.10109
[52] Sams-Dodd, F. (1995) Automation of the Social Interaction Test by a Video-Tracking System: Behavioural Effects of Repeated Phencyclidine Treatment. Journal of Neuroscience Methods, 59, 157-167.
http://dx.doi.org/10.1016/0165-0270(94)00173-E
[53] Niesink, R.J. and Van Ree, J.M. (1982) Short-Term Isolation Increases Social Interactions of Male Rats: A Parametric Analysis. Physiology & Behavior, 29, 819-825.
http://dx.doi.org/10.1016/0031-9384(82)90331-6
[54] Wilson, J.H. (2000) A Conspecific Attenuates Prolactin Responses to Open-Field Exposure in Rats. Hormones and Behavior, 38, 39-43.
http://dx.doi.org/10.1006/hbeh.2000.1600

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