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Commentary Open Access
Volume 3 | Issue 1 | DOI: https://doi.org/10.33696/immunology.3.077

Insulin-like Growth Factor 2: Beyond its Role in Hippocampal-dependent Memory

  • 1Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile
  • 2Center for Geroscience, Brain Health and Metabolism, Santiago, Chile
  • 3Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
  • 4Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Chile
+ Affiliations - Affiliations

*Corresponding Author

Rene L. Vidal, rene.vidal@umayor.cl

Received Date: November 06, 2020

Accepted Date: January 26, 2021

Insulin-like Growth Factor 2 (IGF2) and Its Signaling in the Nervous System

The insulin-like peptides family is composed of insulin, insulin-like growth factor 1 (IGF1), and insulin-like growth factor (IGF2), together with IGF binding proteins (IGFBP1- IGFBP6) [1]. IGF2 is a single-chain secreted protein of 67 amino acids with important functions in fetal growth and development. IGF2 is the less characterized member of this family, and in mice and rats its expression in the brain occurs during embryonic development and adulthood but declines during aging [2]. Alterations in its expression have an impact both in tissue overgrowth as well as reduce growth observed in the Beckwith-Wiedemann syndrome and the Silver-Russell syndrome, respectively [3]. Despite this, IGF2 is the most abundantly expressed IGF in the central nervous system, where it is highly synthesized in the choroid plexus and meninges in adult rat brains [4]. IGF2 binds with high affinity to the IGF2 receptor (IGF2R), which is also a mannose 6-phosphate (M6P) receptor. The IGF2 receptor is a transmembrane glycoprotein containing a short carboxy-terminal cytoplasmatic tail and a long extracytoplasmic domain containing 15 repeating segments [5]. The IGF2R binds M6P-containing ligand and IGF2 in two distinct sites [5]. This receptor has an important role in the intracellular trafficking of lysosomal enzymes from the trans-Golgi network or the extracellular space to lysosomes and also reduces the bioavailability of IGF2 by targeting it to lysosomes [5]. Unlike IGF1 receptor (IGF1R) and insulin receptor (IR), IGF2R does not have intrinsic tyrosine kinase activity but can recruit G proteins, and even though these G-protein-activated pathways are not well characterized in the brain, PKC and phospholipase C are involved in IGF2 actions in the brain [6] and other cell types [7], respectively. IGF2 can also bind, but with less affinity, to the IGF1 receptor (IGF1R) and the isoform A of the insulin receptor (IRA) [3,8], which may activate the signaling pathway downstream these tyrosine kinase receptors. The activation of this pathway modulates gene transcription and activates multiple downstream Kinasesphosphatases branches, affecting key cellular processes such as protein synthesis, autophagy, apoptosis, and resistance to oxidative stress [9].

IGF2 and Its Role in Hippocampal Physiology and Pathophysiology (Figure 1A)

From the early 1990s, it was already described that IGF2 had neuroprotective functions [10]. Moreover, evidence from the past ten years highlights the importance of IGF2 in brain function and brain diseases. As mentioned before, IGF2 levels are high in the hippocampus, and several groups have demonstrated the importance of IGF2 expression in shaping memory. In rats, it has been demonstrated that the expression of IGF2 is physiologically upregulated during hippocampal-mediated learning, and it is important for memory formation and consolidation [11,12]. Administration of recombinant IGF2 also enhanced memory retention and prevented forgetting, processes that were dependent on the binding of IGF2 to its receptor [11]. Together with memory formation, IGF2 has an important role in the extinction of fear memories in the hippocampus, especially those associated with anxiety and mood disorders [13]. Contrary to memory formation, extinction of fear memory was dependent on IGF1R activation [13]. These functions could be explained in part by the fact that IGF2 acts as a regulator of synapse formation and spine maturation in hippocampal neurons, which is mediated by the activation of the IGF2R [14]. In line with these results, it has been observed that intranasal administration of IGF2 ameliorated learning and memory impairments in a mouse model of Fragile X syndrome [15]. Moreover, in aged mice and rats, the hippocampal expression of IGF2 is decreased, and adenoassociated viral vector (AAV)-mediated overexpression of IGF2 or recombinant administration of this peptide in the hippocampus restored hippocampal-dependent memory and dendritic spine density impairments [16,17]. Furthermore, IGF2 expression is also decreased in the hippocampus of Alzheimer’s disease patients and a mouse model of this disease, and AAV-mediated overexpression of IGF2 in the hippocampus of transgenic aged mice reverses memory deficit and restored spine density [16]. Interestingly, IGF2 overexpression reduced amyloid-β plaques in the hippocampus of transgenic mice [16,18], which was mediated by the IGF2R [16].

Interestingly, it has been described an important role of IGF2 in the modulation of anxiety and depressivelike behavior, phenotypes that are also associated with hippocampal function [19]. Treatment of a mouse model of depression with dicholine succinate decreased anxietylike behavior in treated mice, which was accompanied by increased hippocampal IGF2 expression [20]. When IGF2 is ablated in the placenta of wild type mice, this is associated with increased anxiety in their progeny in adulthood [21]. Moreover, in a rat model of depression, IGF2 levels were decreased in the hippocampus, and this phenotype was reversed when IGF2 was overexpressed in this brain area [22]. In line with these findings, treatment of depressive-like mice with the antidepressant ketamine induces an increase in the expression of IGF2 in the hippocampus [23].

Together with its important functions in the hippocampus, IGF2 has a key role in the maintenance of brain neural stem cells (NSCs), which are present in the subventricular zone of the lateral ventricles [24] and the subgranular zone of the dentate gyrus, a region of the hippocampus [25]. It has been shown that IGF2 promotes NSCs self-renewal and stemness in the subventricular zone, which is mediated by IRA, a high-affinity receptor for IGF2 [26,27]. Importantly, IGF2 is highly expressed in NSCs of the dentate gyrus, where it promotes adult neurogenesis both in vitro and in vivo [28,29], an important function of IGF2 that could be therapeutically exploited. The generation of new neurons plays important roles in brain tissue maintenance and function [30], and this process is affected in a variety of brain diseases, including neurodegenerative diseases, mood disorders, epilepsy, and even during aging [31,32]. In conclusion, IGF2 has important functions for brain physiology and in counteracting some of the phenotypes observed in a diverse group of brain diseases

IGF2 and Its Functions Outside the Limits of the Hippocampus (Figure 1B)

Contrary to the vast literature regarding IGF2 function in the physiology and pathophysiology of the hippocampus, only a few reports have linked IGF2 to the amelioration of other nervous system-related diseases that are not linked to hippocampal function. For example, IGF2 is downregulated in the prefrontal cortex of patients with schizophrenia [33], and also hypomethylation of an enhancer within the IGF2 gene has been observed in the prefrontal cortex neurons of schizophrenia patients [34]. Moreover, IGF2 serum levels were decreased in Chinese schizophrenic patients, which were correlated with negative cognitive symptoms in patients [35]. Also, in a mouse model of autism, the systemic injection of IGF2 reversed social, cognitive, and repetitive behaviors [36]. In the peripheral nervous system, it has been shown that IGF2 is highly expressed in resistant motor neurons in amyotrophic lateral sclerosis (ALS) and that the overexpression of IGF2 in human spinal motor neurons of ALS and spinal muscular atrophy patients protected motor neurons from degeneration [32]. Furthermore, AAV-mediated delivery of IGF2 into muscles of ALS transgenic mice preserved motor neurons and induced axonal regeneration and extended mice lifespan [32].

We recently published the impact of IGF2 overexpression in the context of Huntington’s disease (HD). HD is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion mutation in the Htt protein [37]. Although the mutated huntingtin (mHtt) is present in all cell types, medium spiny neurons (MSNs) of the striatum and cortical pyramidal neurons are particularly affected in HD [38]. These alterations trigger a plethora of motor, cognitive, and psychiatric symptoms, which finally causes the death of affected patients. In our study, first we demonstrated that IGF2 overexpression decreases the intracellular levels of mHtt and polyQ79, a peptide used to mimic mHtt aggregation in vitro [39]. This decrease was not due to the activation of macroautophagy or the ubiquitin-proteosome system, but instead, mHtt/ polyQ79 was secreted to the extracellular space under IGF2 administration [39]. The secretion was dependent on the IGF2R and actin cytoskeleton remodeling and was through microvesicles and exosomes [39], but we cannot rule out other possible mechanisms mediating mHtt/ polyQ79 secretion, as described by others [40].

After our interesting results of the significant reduction of mHtt aggregation observed in cells overexpressing IGF2, we developed a strategy to deliver IGF2 into the brain of HD mice using the stereotaxic injection of AAVs to then assess the impact on mHtt levels. For this purpose, we used three different animal models of HD. First, we used an animal model of HD to monitor mHtt aggregation based on the local delivery into the striatum of a large fragment of mHtt of 588 amino acids containing 95 glutamine repetitions fused to monomeric RFP (Htt588Q95- RFP) [41]. We observed a significant decrease in mHtt aggregates and monomeric forms in the striatum of these mice, which was accompanied by increased DARPP-32 levels, a marker of medium spiny neurons viability39. Given these positive results, we also evaluated the effect of IGF2 expression in the striatum of adult YAC128 mice, a mouse model that expresses full-length mHtt with 128 tandem glutamines using an artificial chromosome that contains all endogenous regulatory elements [42]. Besides, we observed a significant reduction of full-length mHtt levels in the striatum, with a near 80% decrease on average [39]. Moreover, we investigated the effect of IGF2 delivery into the ventricle of newborn pups, since stereotaxic injections only transduce a restricted area of the striatum restricting the analysis of motor function. This route of AAV delivery generates a global spreading of viral particles throughout the nervous system. We demonstrated that IGF2 expression significantly reduces the total levels of mHtt in the brain of YAC128 animals, which was accompanied by an improved average of motor performance over time [39]. Finally, we used a third model, the R6/2 mice, a transgenic HD model that expresses exon 1 of human huntingtin containing ~150 CAG repeat [43], which allows the visualization of intracellular mHtt inclusions. Using immunohistochemistry and immunofluorescence analysis, we observed a strong reduction in the content of mHtt-positive inclusions upon AAV-IGF2 administration. These results strongly support the fact that the artificial enforcement of IGF2 expression in the brain reduces mHtt levels in the striatum of different HD models.

One of the most important conclusions drawn from our results is that IGF2 delivery into the striatum has neuroprotective effects and improves motor performance in HD mouse models, adding to the shortlist of publications in which IGF2 has neuroprotective effects outside the hippocampus. What is also important is that IGF2 could be studied in HD models to alleviate other symptoms found in HD patients, which are modeled by HD mice. Motor symptoms in HD patients are usually used to diagnose the disease. However, studies both in humans and in animal models highlight the fact that cognitive, mood, and psychiatric disorders appear before motor symptoms, which in patients have been observed 4-10 years before the onset of motor phenotypes [44]. These disturbances include impulsivity, irritability, anxiety, and depression. In YAC128 mice, cognitive disorders precede motor abnormalities and present similar symptoms and progression of cognitive deficits found in patients [45]. Among the psychiatric disorders present in HD patients and mouse models of HD is anxiety, which can be evaluated using different batteries of behavioral tests [44]. It has been previously described that symptomatic YAC128 mice display increased anxious behavior compared with WT mice [46-48]. Interestingly, the hippocampus is a core brain structure in the genesis of anxiety [19], and alterations of neurogenesis in the hippocampal dentate gyrus have been directly associated with anxious behavior. Furthermore, it has been shown that YAC128 mice have decreased hippocampal cell proliferation and neuronal differentiation [49]. As described previously, several studies highlight the important role of IGF2 in hippocampal neurogenesis. IGF2 is upregulated in neural stem cells that will divide and form new neurons in the dentate gyrus of the hippocampus [28], and also participates in synapse formation and spine maturation in hippocampal neurons [14]. These findings strongly suggest that overexpression of IGF2 in the hippocampus of HD mouse models would have a positive impact in decreasing anxiety in these mice. Moreover, the effect of IGF2 delivery in other brain areas typically involved in anxious behavior, such as the amygdala, medial prefrontal cortex, among others needs further investigation.

The hippocampal function has widely been associated with memory formation ref. The YAC128 mouse model shows impaired learning and memory starting at 8 months of age, which progressively worsen [45]. This phenotype has been attributed to reduced hippocampal dentate gyrus neurogenesis, as previously described [49]. Using our YAC128 mouse model, we did not observe impaired spatial learning and memory, which could be caused by the different genetic background of the mice used in this study. Several investigations have demonstrated the importance of IGF2 in memory enhancement and consolidation11, and its effect in reversing memory deficits and hippocampal synaptic alterations in mouse models of AD [50]. Therefore, we speculate that IGF2 expression in mice would recover learning and memory in HD mouse models.

Concluding Remarks

Over the past 10 years, important evidence has highlighted the important function of IGF2 in brain physiology and in pathophysiological conditions. Several findings have demonstrated the crucial function of IGF2 in hippocampal memory formation and extinction, neurogenesis, and spine and dendrites formation. Beyond the hippocampal boundaries, IGF2 has shown to be neuroprotective for motor and striatal neurons under pathological conditions. It is clear that the neuroprotective effects of IGF2 must be studied in other brain areas affected in different brain diseases, which we speculate would have beneficial effects in other cognitive symptoms beyond hippocampaldependent memory. Anxiety, obsessive-compulsive behaviors, addictions, depression, and other cognitive disabilities could be targeted by the treatment with IGF2. Given that IGF2 crosses the blood-brain, it appears as an interesting candidate for potential translational applications, where its route of administration can be noninvasive for patients and it could reach all brain areas or other organs affected by one of the many diseases present in humans. Although IGF2 has been the less studied member of the IGF peptide family for years, it is time for us to focus our attention on this soluble factor that has been shown to be an important actor in many brain conditions.

Funding

This work was directly funded by ANID/FONDAP program 15150012 (R.L.V.), Millennium Institute P09- 015-F (R.L.V.), FONDECYT 1191003 (R.L.V.), CONICYT Ph.D. fellowship 21160843 (P.T-E.).

References

1. Lewitt MS, Boyd GW. The Role of Insulin-Like Growth Factors and Insulin-Like Growth Factor–Binding Proteins in the Nervous System. Biochemistry Insights. 2019 Apr;12:1178626419842176.

2. Kitraki E, Bozas E, Philippdis H, Stylianopoulou F. Aging-related changes in IGF-II and c-fos gene expression in the rat brain. International Journal of Developmental Neuroscience. 1993 Feb;11(1):1-9.

3. Azzi S, Abi Habib W, Netchine I. Beckwith–Wiedemann and Russell–Silver Syndromes: From new molecular insights to the comprehension of imprinting regulation. Current Opinion in Endocrinology, Diabetes and Obesity. 2014 Feb 1;21(1):30-8.

4. Stylianopoulou F, Herbert J, Soares MB, Efstratiadis A. Expression of the insulin-like growth factor II gene in the choroid plexus and the leptomeninges of the adult rat central nervous system. Proceedings of the National Academy of Sciences. 1988 Jan 1;85(1):141-5.

5. Hawkes C, Kar S. The insulin-like growth factor-II/ mannose-6-phosphate receptor: structure, distribution and function in the central nervous system. Brain Research Reviews. 2004 Mar 1;44(2-3):117-40.

6. Hawkes C, Jhamandas JH, Harris KH, Fu W, MacDonald RG, Kar S. Single transmembrane domain insulin-like growth factor-II/mannose-6-phosphate receptor regulates central cholinergic function by activating a G-proteinsensitive, protein kinase C-dependent pathway. Journal of Neuroscience. 2006 Jan 11;26(2):585-96.

7. Poiraudeau S, Lieberherr M, Kergosie N, Corvol MT. Different mechanisms are involved in intracellular calcium increase by insulin-like growth factors 1 and 2 in articular chondrocytes: Voltage-gated calcium channels, and/or phospholipase C coupled to a pertussis-sensitive G-protein. Journal of Cellular Biochemistry. 1997 Mar 1;64(3):414-22.

8. Fernandez AM, Torres-Alemán I. The many faces of insulin-like peptide signalling in the brain. Nature Reviews Neuroscience. 2012 Apr;13(4):225-39.

9. Hakuno F, Takahashi SI. 40 years of IGF1: IGF1 receptor signaling pathways. Journal of Molecular Endocrinology. 2018 Jul 1;61(1):T69-86.

10. Cheng B, Mattson MP. IGF-I and IGF-II protect cultured hippocampal and septal neurons against calciummediated hypoglycemic damage. Journal of Neuroscience. 1992 Apr 1;12(4):1558-66.

11. Chen DY, Stern SA, Garcia-Osta A, Saunier-Rebori B, Pollonini G, Bambah-Mukku D, et al. A critical role for IGF-II in memory consolidation and enhancement. Nature. 2011 Jan;469(7331):491-7.

12. Stern SA, Kohtz AS, Pollonini G, Alberini CM. Enhancement of memories by systemic administration of insulin-like growth factor II. Neuropsychopharmacology. 2014 Aug;39(9):2179-90.

13. Agis-Balboa RC, Arcos-Diaz D, Wittnam J, Govindarajan N, Blom K, Burkhardt S, et al. A hippocampal insulin-growth factor 2 pathway regulates the extinction of fear memories. The EMBO Journal. 2011 Oct 5;30(19):4071-83.

14. Schmeisser MJ, Baumann B, Johannsen S, Vindedal GF, Jensen V, Hvalby ØC, et al. IκB kinase/nuclear factor κB-dependent insulin-like growth factor 2 (Igf2) expression regulates synapse formation and spine maturation via Igf2 receptor signaling. Journal of Neuroscience. 2012 Apr 18;32(16):5688-703.

15. Pardo M, Cheng Y, Velmeshev D, Magistri M, Eldar-Finkelman H, Martinez A, et al. Intranasal siRNA administration reveals IGF2 deficiency contributes to impaired cognition in Fragile X syndrome mice. JCI Insight. 2017 Mar 23;2(6).

16. Pascual-Lucas M, Viana da Silva S, Di Scala M, Garcia-Barroso C, González-Aseguinolaza G, Mulle C, et al. Insulin-like growth factor 2 reverses memory and synaptic deficits in APP transgenic mice. EMBO Molecular Medicine. 2014 Oct;6(10):1246-62.

17. Steinmetz AB, Johnson SA, Iannitelli DE, Pollonini G, Alberini CM. Insulin-like growth factor 2 rescues agingrelated memory loss in rats. Neurobiology of Aging. 2016 Aug 1;44:9-21.

18. Mellott TJ, Pender SM, Burke RM, Langley EA, Blusztajn JK. IGF2 ameliorates amyloidosis, increases cholinergic marker expression and raises BMP9 and neurotrophin levels in the hippocampus of the APPswePS1dE9 Alzheimer’s disease model mice. PloS One. 2014 Apr 14;9(4):e94287.

19. Bannerman DM, Rawlins JN, McHugh SB, Deacon RM, Yee BK, Bast T, Zhang WN, Pothuizen HH, Feldon J. Regional dissociations within the hippocampus—memory and anxiety. Neuroscience & Biobehavioral Reviews. 2004 May 1;28(3):273-83.

20. Cline BH, Steinbusch HW, Malin D, Revishchin AV, Pavlova GV, Cespuglio R, et al. The neuronal insulin sensitizer dicholine succinate reduces stress-induced depressive traits and memory deficit: possible role of insulin-like growth factor 2. BMC Neuroscience. 2012 Dec;13(1):1-4.

21. Mikaelsson MA, Constância M, Dent CL, Wilkinson LS, Humby T. Placental programming of anxiety in adulthood revealed by Igf2-null models. Nature Communications. 2013 Aug 6;4(1):1-9.

22. Luo YW, Xu Y, Cao WY, Zhong XL, Duan J, Wang XQ, et al. Insulin-like growth factor 2 mitigates depressive behavior in a rat model of chronic stress. Neuropharmacology. 2015 Feb 1;89:318-24.

23. Grieco SF, Cheng Y, Eldar-Finkelman H, Jope RS, Beurel E. Up-regulation of insulin-like growth factor 2 by ketamine requires glycogen synthase kinase-3 inhibition. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2017 Jan 4;72:49-54.

24. Lois C, Alvarez-Buylla A. Long-distance neuronal migration in the adult mammalian brain. Science. 1994 May 20;264(5162):1145-8.

25. Kuhn HG, Dickinson-Anson H, Gage FH. Neurogenesis in the dentate gyrus of the adult rat: agerelated decrease of neuronal progenitor proliferation. Journal of Neuroscience. 1996 Mar 15;16(6):2027-33.

26. Ziegler AN, Schneider JS, Qin M, Tyler WA, Pintar JE, Fraidenraich D, et al. IGF-II promotes stemness of neural restricted precursors. Stem Cells. 2012 Jun;30(6):1265-76.

27. Ziegler AN, Chidambaram S, Forbes BE, Wood TL, Levison SW. Insulin-like growth factor-II (IGF-II) and IGF-II analogs with enhanced insulin receptor-a binding affinity promote neural stem cell expansion. Journal of Biological Chemistry. 2014 Feb 21;289(8):4626-33.

28. Bracko O, Singer T, Aigner S, Knobloch M, Winner B, Ray J, et al. Gene expression profiling of neural stem cells and their neuronal progeny reveals IGF2 as a regulator of adult hippocampal neurogenesis. Journal of Neuroscience. 2012 Mar 7;32(10):3376-87.

29. Ferrón SR, Radford EJ, Domingo-Muelas A, Kleine I, Ramme A, Gray D, et al. Differential genomic imprinting regulates paracrine and autocrine roles of IGF2 in mouse adult neurogenesis. Nature Communications. 2015 Sep 15;6(1):1-2.

30. Zhao C, Deng W, Gage FH. Mechanisms and functional implications of adult neurogenesis. Cell. 2008 Feb 22;132(4):645-60.

31. Toda T, Parylak SL, Linker SB, Gage FH. The role of adult hippocampal neurogenesis in brain health and disease. Molecular Psychiatry. 2019 Jan;24(1):67-87.

32. Allodi I, Comley L, Nichterwitz S, Nizzardo M, Simone C, Benitez JA, et al. Differential neuronal vulnerability identifies IGF-2 as a protective factor in ALS. Scientific Reports. 2016 May 16;6(1):1-4.

33. Fromer M, Roussos P, Sieberts SK, Johnson JS, Kavanagh DH, Perumal TM, et al. Gene expression elucidates functional impact of polygenic risk for schizophrenia. Nature Neuroscience. 2016 Nov;19(11):1442-53.

34. Pai S, Li P, Killinger B, Marshall L, Jia P, Liao J, et al. Differential methylation of enhancer at IGF2 is associated with abnormal dopamine synthesis in major psychosis. Nature Communications. 2019 May 3;10(1):1-2.

35. Yang YJ, Luo T, Zhao Y, Jiang SZ, Xiong JW, Zhan JQ, et al. Altered insulin-like growth factor-2 signaling is associated with psychopathology and cognitive deficits in patients with schizophrenia. PloS One. 2020 Mar 19;15(3):e0226688.

36. Steinmetz AB, Stern SA, Kohtz AS, Descalzi G, Alberini CM. Insulin-like growth factor II targets the mTOR pathway to reverse autism-like phenotypes in mice. Journal of Neuroscience. 2018 Jan 24;38(4):1015-29.

37. The Huntington’s Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell. 1993 Mar 26;72(6):971-83.

38. Han I, You Y, Kordower JH, Brady ST, Morfini GA. Differential vulnerability of neurons in Huntington’s disease: the role of cell type-specific features. Journal of Neurochemistry. 2010 Jun;113(5):1073-91.

39. García-Huerta P, Troncoso-Escudero P, Wu D, Thiruvalluvan A, Cisternas-Olmedo M, Henríquez DR, et al. Insulin-like growth factor 2 (IGF2) protects against Huntington’s disease through the extracellular disposal of protein aggregates. Acta Neuropathologica. 2020 Nov;140(5):737-64.

40. Trajkovic K, Jeong H, Krainc D. Mutant huntingtin is secreted via a late endosomal/lysosomal unconventional secretory pathway. Journal of Neuroscience. 2017 Sep 13;37(37):9000-12.

41. Zuleta A, Vidal RL, Armentano D, Parsons G, Hetz C. AAV-mediated delivery of the transcription factor XBP1s into the striatum reduces mutant Huntingtin aggregation in a mouse model of Huntington’s disease. Biochemical and Biophysical Research Communications. 2012 Apr 13;420(3):558-63.

42. Slow EJ, Van Raamsdonk J, Rogers D, Coleman SH, Graham RK, Deng Y, et al. Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease. Human molecular genetics. 2003 Jul 1;12(13):1555-67.

43. Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, et al. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell. 1996 Nov 1;87(3):493-506.

44. Pla P, Orvoen S, Saudou F, David DJ, Humbert S. Mood disorders in Huntington’s disease: from behavior to cellular and molecular mechanisms. Frontiers in Behavioral Neuroscience. 2014 Apr 23;8:135.

45. Van Raamsdonk JM, Pearson J, Slow EJ, Hossain SM, Leavitt BR, Hayden MR. Cognitive dysfunction precedes neuropathology and motor abnormalities in the YAC128 mouse model of Huntington’s disease. Journal of Neuroscience. 2005 Apr 20;25(16):4169-80.

46. Southwell AL, Ko J, Patterson PH. Intrabody gene therapy ameliorates motor, cognitive, and neuropathological symptoms in multiple mouse models of Huntington’s disease. Journal of Neuroscience. 2009 Oct 28;29(43):13589-602.

47. Chiu CT, Liu G, Leeds P, Chuang DM. Combined treatment with the mood stabilizers lithium and valproate produces multiple beneficial effects in transgenic mouse models of Huntington’s disease. Neuropsychopharmacology. 2011 Nov;36(12):2406-21.

48. Garcia-Miralles M, Geva M, Tan JY, Yusof NA, Cha Y, Kusko R, et al. Early pridopidine treatment improves behavioral and transcriptional deficits in YAC128 Huntington disease mice. JCI Insight. 2017 Dec 7;2(23).

49. Simpson JM, Gil-Mohapel J, Pouladi MA, Ghilan M, Xie Y, Hayden MR, et al. Altered adult hippocampal neurogenesis in the YAC128 transgenic mouse model of Huntington disease. Neurobiology of Disease. 2011 Feb 1;41(2):249-60.

50. Pascual-Lucas M, Viana da Silva S, Di Scala M, Garcia-Barroso C, González-Aseguinolaza G, Mulle C, et al. Insulin-like growth factor 2 reverses memory and synaptic deficits in APP transgenic mice. EMBO Molecular Medicine. 2014 Oct;6(10):1246-62.

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