<%server.execute "isdev.asp"%> Synaptogenesis in the cerebellum of offspring born to diabetic mothers Hami J, Vafaei-Nezhad S, Sadeghi A, Ghaemi K, Taheri MMH, Fereidouni M, Ivar G, Hosseini M - J Pediatr Neurosci
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Year : 2017  |  Volume : 12  |  Issue : 3  |  Page : 215-221

Synaptogenesis in the cerebellum of offspring born to diabetic mothers

1 Cellular and Molecular Research Center; Department of Anatomy, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran
2 Department of Neurosurgery, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran
3 Department of Anatomy, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran
4 Cellular and Molecular Research Center; Department of Immunology, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran
5 Department of Public Health, Research Centre of Experimental Medicine, Birjand University of Medical Sciences, Birjand, Iran

Date of Web Publication14-Nov-2017

Correspondence Address:
Javad Hami
Department of Anatomy, School of Medicine, Birjand University of Medical Sciences, Birjand
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jpn.JPN_144_16

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There is increasing evidence that maternal diabetes mellitus during the pregnancy is associated with a higher risk of neurodevelopmental and neurofunctional anomalies including motor dysfunctions, learning deficits, and behavioral problems in offspring. The cerebellum is a part of the brain that has long been recognized as a center of movement balance and motor coordination. Moreover, recent studies in humans and animals have also implicated the cerebellum in cognitive processing, sensory discrimination, attention, and learning and memory. Synaptogenesis is one of the most crucial events during the development of the central nervous system. Synaptophysin (SYP) is an integral membrane protein of synaptic vesicles and is considered to be a marker for synaptic density and synaptogenesis. Here, we review the manuscripts focusing on the negative impacts of maternal diabetes in pregnancy on the expression or localization of SYP in the developing cerebellar cortex. We believe that the alteration in synaptogenesis or synapse density may be part of the cascade of events through which diabetes in pregnant women affects the newborn's cerebellum.

Keywords: Cerebellum, maternal diabetes, synaptogenesis, synaptophysin

How to cite this article:
Hami J, Vafaei-Nezhad S, Sadeghi A, Ghaemi K, Taheri MMH, Fereidouni M, Ivar G, Hosseini M. Synaptogenesis in the cerebellum of offspring born to diabetic mothers. J Pediatr Neurosci 2017;12:215-21

How to cite this URL:
Hami J, Vafaei-Nezhad S, Sadeghi A, Ghaemi K, Taheri MMH, Fereidouni M, Ivar G, Hosseini M. Synaptogenesis in the cerebellum of offspring born to diabetic mothers. J Pediatr Neurosci [serial online] 2017 [cited 2020 Nov 26];12:215-21. Available from: https://www.pediatricneurosciences.com/text.asp?2017/12/3/215/218227

   Introduction Top

Diabetes mellitus during pregnancy period is one of the most common metabolic complications that can be classified into two categories: pregestational or gestational diabetes.[1],[2],[3],[4],[5],[6],[7] This metabolic disorder occurs in 3%–5% of pregnancies.[8],[9] Nevertheless, the prevalence of diabetes in pregnancy has been reported to range between <1% to about 14% in different societies.[2],[10],[11],[12] An increasing number of evidence clearly showed that children born to diabetic mothers are in increased risk of fetal and neonatal anomalies including central nervous system (CNS) abnormalities[9],[13] which results in increased infant mortality and morbidity rates.[2],[7],[9],[14],[15] Previous investigations also report that maternal diabetes is associated with a higher risk of long-lasting neurological impairment that is manifested as deficits in balance and motor coordination, hyperactivity, impairments in attention and memory, and altered social behavior in offspring.[13],[16],[17],[18],[19],[20],[21]

The functional and structural effects of diabetes in pregnancy on the developing CNS have been studied in both human and experimental models.[22],[23] Although, the precise mechanisms that diabetes in pregnancy can affect the development and function of the nervous system remain to be defined.[2],[5],[7],[22],[23],[24] In humans, children from mothers with diabetes during the pregnancy may exhibit abnormalities, which include learning defects, motor difficulties, attention deficit, and also the risk of developing schizophrenia.[19],[25],[26] Babiker indicated a higher prevalence of developmental delay and behavioral problems in children born to diabetic women. In that study, growth motor skills and language delay were the major development areas of concern they could link between maternal diabetes and development.[17] There is also evidence demonstrating a negative relationship between the performances of the children born to diabetic mothers with the severity of maternal hyperglycemia.[7],[27],[28] Recent studies found negative effects of maternal diabetes during pregnancy on the development of cerebellar cortex and also the expression and localization of insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor (InsR), as two regulators of CNS development, in the cerebellum and hippocampus of neonatal rats as a probable mechanism for the neurodevelopmental and neurobehavioral impairments observed in diabetic mothers' offspring.[14],[16],[29],[30],[31] Other investigation by Hami et al. also evaluated the effects of maternal diabetes on the developing cerebellum of rats. They estimated cerebellar volume, the thickness and the number of cells in the different layers of the cerebellar cortex. Their results have been shown a significant reduction in the cerebellar volume and the thickness of various developing cerebellar cortex such as external granule layer (EGL), molecular layer (ML), and internal granule layer (IGL) in the offspring born to diabetic animals. They also reported that diabetes in pregnancy disrupts the morphogenesis of developing cerebellar cortex and believed that this dysmorphogenesis may be part of the cascade of events through which maternal diabetes affects motor coordination and social behaviors in offspring.[32] A study by Khaksar et al. also indicated the detrimental effects of diabetes during pregnancy period on the thickness of cerebellar cortex in neonatal rats.[33] Overall, there are multiple lines of evidence suggesting that diabetes in pregnancy can cause neurofunctional and neurostructural abnormalities in the offspring by alteration of many developmental events such as neurogenesis, migration, and differentiation.[16],[34]

With regards to the importance of synaptogenesis in developing cerebellum, here, we have reviewed the related articles focusing on the effects of maternal diabetes during pregnancy on the expression or localization of synaptophysin (SYP) in the developing cerebellar cortex of neonatal rats. We believe that the neurodevelopmental and neurofunctional impairments observed in the children born to diabetic mothers may be mediated, at least in part, via alterations in expression and localization of SYP in the developing cerebellum.

   Discussion Top

Synapse and synaptogenesis

Synapses are specialized connections between neurons permitting the controlled transfer of chemical/electrical signals between presynaptic neuronal cells and postsynaptic target neurons.[35] Adequate synapse function is an essential prerequisite of all neuronal processing.[35] True connection between neurons is fundamental to the physiological function of the nervous system,[36],[37] and perception, learning, and memory are only possible when the nervous system is functioning normally.[38]

During the development of CNS, synaptogenesis-formation and maturation of synaptic contacts-is one of the most crucial events that is represents the final step of neuronal differentiation.[2],[23],[39],[40],[41] Synaptogenesis begins early in the embryo and extends well into postnatal life.[42],[43] In mammals, the period and length of newly synapse formation is vary widely from species to species which is in human neocortex occurs during the third trimester of gestation and the first 2 postnatal years, whereas in rodents, the first 2 weeks after birth represent the most active phase of synaptogenesis.[39],[40],[44],[45] Moreover, the formation of a functional synapse is a complex process that involves multiple stages such as axon guidance, synapse formation, synapse maintenance (stabilization), and activity-dependent synapse elimination.[42],[46],[47],[48]

Chemical synapses are best characterized as asymmetric neuronal junctions which are composed of three compartments: The presynaptic bouton, the synaptic cleft and the postsynaptic apparatus.[23],[49],[50],[51] Presynaptic boutons generally form along the long axis of axons and are filled with anywhere from neurotransmitter substances filled synaptic vesicles such as glutamate, acetylcholine, glycine, dopamine, serotonin, adrenalin, noradrenalin, or gamma amino butyric acid. These vesicles are often released in an activity dependent manner[49],[52],[53] into the small space between the pre- and post-synaptic membranes also called synaptic cleft. In the synaptic cleft, they bind and activate neurotransmitter receptors within the postsynaptic membrane.[2],[23],[35],[54],[55] In fact, the most principal function in the presynaptic buttons is the regulated release of neurotransmitter in a tightly regulated process called exocytosis which is accomplished through the fusions of synaptic vesicles with the presynaptic membrane.[23],[54],[56] Several lines of studies were carried out to characterize the components of the synaptic vesicle membrane and found a number of proteins, including SYP, synaptotagmin, and synaptobrevin that functions as the regulators of exocytosis.[2],[52],[57],[58],[59]

SYP is an integral membrane glycoprotein of synaptic vesicles, with a molecular weight of 38 kDa containing four membrane-spanning domains located on the cytoplasmic surface.[2],[23],[60],[61] It is a major component of synaptic vesicles membrane and involved in the release of neurotransmitters and formation and recycling of synaptic vesicles.[2],[23],[60],[62],[63],[64] SYP was one of the first proteins to be characterized in the synaptic vesicles membrane and accounts for about 7%–10% of total synaptic vesicle proteins.[23],[59],[63],[65],[66] Based on its structure, it was proposed that SYP forms a channel in the synaptic vesicle membrane and acts as the major Ca2+ binding protein in synaptic vesicles. Therefore, it is suggested that SYP is involved in calcium dependent synaptic vesicle exocytosis.[60],[64],[67],[68] In the previous investigations, SYP has also been considered as a reliable marker for synaptic density and synaptogenesis.[2],[23],[69],[70],[71],[72]

The expression of SYP already starts during early neurogenesis in embryonic developing brain and is greatly up-regulated during synaptogenesis.[23],[73],[74] There is also evidence demonstrating that upregulation of SYP expression may contribute to the mechanisms underlying learning and memory.[75],[76],[77] Conversely, aberrant SYP expression has been associated with several psychiatric disorders and neurodegenerative diseases, such as, Parkinson disease, and Alzheimer's disease.[2],[23],[78],[79],[80] Earlier studies on aging and neurodegenerative disorders have correlated change in SYP immunoreactivity with loss or increase in synaptic densities.[62],[76],[81] In a study by Thome et al., the researchers revealed that stress exposure leads to the reduction in hippocampal expression of SYP.[82]


The cerebellum is one of the most studied parts of the brain located at the back of the brain, underlying the temporal and occipital lobes of the brain.[83],[84],[85] For a long time, the cerebellum has been considered to be a critical brain structure for the coordination and control of voluntary movements.[2],[13],[16],[29],[86] However, recent evidence indicates that the cerebellum also plays a role in cognitive, behavioral, and emotional functions.[13],[29],[87] Several lines of studies clearly indicated that the cerebellum may be involved in a variety of nonmotor functions, including sensory discrimination, working memory, semantic association, attention, and verbal learning and memory.[88] Anyway, arranged three-layered cerebellar cortex and well-defined afferent and efferent fiber connections make it a favorite field for research on development and fiber connections of the CNS.[83],[84]

The cerebellum in rats develops over a long period, extending from the early embryonic period until the first postnatal weeks. This protracted development makes it vulnerable to a broad spectrum of developmental abnormalities.[23],[83],[89] The development of the cerebellum occurs in four basic steps: (1) characterization of the cerebellar territory at the boundary between midbrain and hindbrain; (2) formation of two compartments for cell proliferation including the Purkinje cells which arise from the ventricular zone of the mesencephalic alar plate and granule cell precursors which formed from the upper rhombic lip; (3) migration of the granule cells: granule precursor cells form the EGL, from which granule cells migrate inward to their definite position in the IGL, and (4) formation of cerebellar circuitry and further differentiation.[90],[91],[92],[93],[94],[95]

This phenomenon in the developing rat cerebellar cortex has been studied in detail by Altman and Bayer.[90],[96],[97] Immediately after birth, granule cells are observed to be aligned outside of the developing cerebellum, known as EGL. At the next postnatal days, the granule cells extrude processes that move toward Purkinje cells. Finally, the cell bodies of the granule cells pass through the layer of Purkinje cells to form IGL. At the same time, Purkinje cells also develop dendrites, and begin to form synapses with parallel fibers, and form the ML. Approximately 2 weeks after birth, formation of the ML is completed, and the cerebellum shows almost the same morphology as that of the adult rat.[13],[23],[90],[96],[97]

Effects of maternal diabetes in pregnancy on synaptogenesis in developing cerebellum

The adverse impacts of diabetes during pregnancy on the developing CNS of the fetuses and newborns are already well documented.[6],[7],[17],[98],[99],[100],[101] However, there is limited number of studies that specially focused on the impacts of diabetes during pregnancy on synaptogenesis in the developing cerebellum of offspring. The earlier investigations demonstrated a moderate disturbance in memory and learning and complex information processing of offspring born to mothers who had diabetes during their pregnancy.[102],[103] Rizzo et al., in their investigation demonstrated a significant correlation between gestational diabetes and lower IQ in children.[104]

Other studies also revealed a negative relationship between the severity of maternal hyperglycemia during and the gestation and the performance of the children on various developmental and behavioral tests.[7],[19],[105],[106],[107] A research by Ornoy et al. reported that children younger than 9 years, born to diabetic women, had a higher rate of attention deficit, lower cognitive scores, and lower gross and fine motor achievements.[108] In another study, Rizzo et al. revealed a striking relationship between second- and third-trimester glycemic control and poorer infant responses on the Brazelton Neonatal Behavioral Assessment Scale.[104] Taken together, the existing evidence not only demonstrate the teratogenic effect of maternal diabetes on the development of offspring's nervous system but also provide the perhaps earliest indicator of postnatal CNS problems reflected in intellectual, behavioral and movement anomalies exhibited by children of mothers with diabetes.[7],[18],[27],[28],[98],[107] Nevertheless, no report can fully explore the molecular mechanisms of maternal diabetes-induced neurodevelopmental and neurofunctional abnormalities.[2],[7],[23]

In a recent study by Hami et al., the authors evaluated the effects of diabetes in pregnancy on the expression and localization of SYP during the development of cerebellum in the rat offspring. The authors found no significant alterations in the cerebellar expression/localization of SYP in neonate's born to diabetic animals, immediately after birth. Nevertheless, they reported that the expression of SYP was significantly down-regulated at 1- and 2-weeks-old of age rats. In addition, their results also demonstrated that the localization of SYP protein was strikingly reduced in all three distinct layers of cerebellar cortex of neonates born to diabetic animals, especially at postnatal day (P) 14.[23] Another recent study by Vafaei-Nezhad et al. indicated that there were no differences in the SYP expression/localization in the hippocampus of neonates born to diabetic dams at P0; the researchers also indicated that the gestational diabetes in pregnancy is associated with a significant downregulation in hippocampal expression/localization of SYP in the neonatal rats at P7, and P14.[2] Since SYP and other synaptic vesicle proteins have been implicated in the mechanisms of cellular plasticity underlying learning;[62],[75],[76],[77],[81] the early decrease in SYP expression/localization may reflect a downregulation of synaptic function and may be related to the reduction in synaptic density and might disrupt the development and function of cerebellum.[23],[76],[77],[79],[109]

Taken together, The exact mechanisms through which diabetes in pregnancy affects fetal CNS development and function are not completely understood, the conclusion from a review of numerous studies is that maternal hyperglycemia during pregnancy may be a major teratogenic factor.[7],[13],[31] The remarkable thing about the glucose, in contrast to insulin, is that Glucose can freely cross the placental barrier; thus, maternal hyperglycemia during gestational period causes fetal hyperglycemia.[7],[23],[110],[111] Fetal hyperglycemia stimulates the developing,[112] resulting to in utero fetal hyperinsulinemia. On separation of the newborn from the mother, the glucose former no longer is supported by placental glucose transfer, may develop neonatal hypoglycemia.[7],[15]

In addition, some researchers argue that the maternal metabolic condition, in combination with a disturbed fetal metabolism, may have teratogenic consequences and may increase the risk of fetal abnormalities in diabetic pregnancies.[24],[104] Excess fetal reactive oxygen species have also been implicated in the pathogenesis of diabetes-induced congenital anomalies in CNS.[113],[114],[115],[116]

   Conclusion Top

In these studies using SYP, a marker of synaptic density and synaptic vesicle formation, it was shown that maternal hyperglycemia, in combination with neonatal hyperinsulinemia was able to decline synaptogenesis in the offspring's cerebellar cortex. This alteration may result in a delay in normal cerebellar development and function and could be a reason for the structural, behavioral, and cognitive abnormalities observed in the offspring of diabetic mothers.

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Conflicts of interest

There are no conflicts of interest.

   References Top

Sheffield JS, Butler-Koster EL, Casey BM, McIntire DD, Leveno KJ. Maternal diabetes mellitus and infant malformations. Obstet Gynecol 2002;100:925-30.  Back to cited text no. 1
Vafaei-Nezhad S, Hami J, Sadeghi A, Ghaemi K, Hosseini M, Abedini MR, et al. The impacts of diabetes in pregnancy on hippocampal synaptogenesis in rat neonates. Neuroscience 2016;318:122-33.  Back to cited text no. 2
Lynch CP, Baker N, Korte JE, Mauldin JG, Mayorga ME, Hunt KJ, et al. Increasing prevalence of diabetes during pregnancy in South Carolina. J Womens Health (Larchmt) 2015;24:316-23.  Back to cited text no. 3
ter Braak EW, Evers IM, Willem Erkelens D, Visser GH. Maternal hypoglycemia during pregnancy in type 1 diabetes: Maternal and fetal consequences. Diabetes Metab Res Rev 2002;18:96-105.  Back to cited text no. 4
Eidelman AI, Samueloff A. The pathophysiology of the fetus of the diabetic mother. Semin Perinatol 2002;26:232-6.  Back to cited text no. 5
Aerts L, Holemans K, Van Assche FA. Maternal diabetes during pregnancy: Consequences for the offspring. Diabetes Metab Rev 1990;6:147-67.  Back to cited text no. 6
Hami J, Shojae F, Vafaee-Nezhad S, Lotfi N, Kheradmand H, Haghir H, et al. Some of the experimental and clinical aspects of the effects of the maternal diabetes on developing hippocampus. World J Diabetes 2015;6:412-22.  Back to cited text no. 7
Ben-Haroush A, Yogev Y, Hod M. Epidemiology of gestational diabetes mellitus and its association with type 2 diabetes. Diabet Med 2004;21:103-13.  Back to cited text no. 8
Hami J, Kerachian MA, Karimi R, Haghir H, Sadr-Nabavi A. Effects of streptozotocin-induced type 1 maternal diabetes on PI3K/AKT signaling pathway in the hippocampus of rat neonates. J Recept Signal Transduct Res 2016;36:254-60.  Back to cited text no. 9
Mwanri AW, Kinabo J, Ramaiya K, Feskens EJ. Gestational diabetes mellitus in Sub-Saharan Africa: Systematic review and metaregression on prevalence and risk factors. Trop Med Int Health 2015;20:983-1002.  Back to cited text no. 10
Mahalakshmi MM, Bhavadharini B, Kumar M, Anjana RM, Shah SS, Bridgette A, et al. Clinical profile, outcomes, and progression to type 2 diabetes among Indian women with gestational diabetes mellitus seen at a diabetes center in South India. Indian J Endocrinol Metab 2014;18:400-6.  Back to cited text no. 11
DeSisto CL, Kim SY, Sharma AJ. Prevalence estimates of gestational diabetes mellitus in the United States, pregnancy risk assessment monitoring system (PRAMS), 2007-2010. Prev Chronic Dis 2014;11:E104.  Back to cited text no. 12
Hami J, Vafaei-Nezhad S, Haghir D, Haghir H. Insulin-like growth factor-1 receptor is differentially distributed in developing cerebellar cortex of rats born to diabetic mothers. J Mol Neurosci 2016;58:221-32.  Back to cited text no. 13
Hami J, Karimi R, Haghir H, Gholamin M, Sadr-Nabavi A. Diabetes in pregnancy adversely affects the expression of glycogen synthase kinase-3β in the hippocampus of rat neonates. J Mol Neurosci 2015;57:273-81.  Back to cited text no. 14
Schwartz R, Teramo KA. Effects of diabetic pregnancy on the fetus and newborn. Semin Perinatol 2000;24:120-35.  Back to cited text no. 15
Haghir H, Rezaee AA, Sankian M, Kheradmand H, Hami J. The effects of induced type-I diabetes on developmental regulation of insulin & insulin like growth factor-1 (IGF-1) receptors in the cerebellum of rat neonates. Metab Brain Dis 2013;28:397-410.  Back to cited text no. 16
Babiker O. Long-term effects of maternal diabetes on their offspring development and behaviours. Sudan J Paediatr 2007;8:133-46.  Back to cited text no. 17
Georgieff MK. The effect of maternal diabetes during pregnancy on the neurodevelopment of offspring. Minn Med 2006;89:44-7.  Back to cited text no. 18
Delascio Lopes C, Sinigaglia-Coimbra R, Mazzola J, Camano L, Mattar R. Neurofunctional evaluation of young male offspring of rat dams with diabetes induced by streptozotocin. ISRN Endocrinol 2011;2011:480656.  Back to cited text no. 19
Nelson CA, Wewerka S, Thomas KM, Tribby-Walbridge S, deRegnier R, Georgieff M, et al. Neurocognitive sequelae of infants of diabetic mothers. Behav Neurosci 2000;114:950-6.  Back to cited text no. 20
Ornoy A. Growth and neurodevelopmental outcome of children born to mothers with pregestational and gestational diabetes. Pediatr Endocrinol Rev 2005;3:104-13.  Back to cited text no. 21
Sadler TW. Effects of maternal diabetes on early embryogenesis: II. Hyperglycemia-induced exencephaly. Teratology 1980;21:349-56.  Back to cited text no. 22
Hami J, Vafaei-Nezhad S, Ivar G, Sadeghi A, Ghaemi K, Mostafavizadeh M, et al. Altered expression and localization of synaptophysin in developing cerebellar cortex of neonatal rats due to maternal diabetes mellitus. Metab Brain Dis 2016;31:1369-80.  Back to cited text no. 23
Styrud J, Thunberg L, Nybacka O, Eriksson UJ. Correlations between maternal metabolism and deranged development in the offspring of normal and diabetic rats. Pediatr Res 1995;37:343-53.  Back to cited text no. 24
Cannon M, Caspi A, Moffitt TE, Harrington H, Taylor A, Murray RM, et al. Evidence for early-childhood, pan-developmental impairment specific to schizophreniform disorder: Results from a longitudinal birth cohort. Arch Gen Psychiatry 2002;59:449-56.  Back to cited text no. 25
Isohanni M, Jones PB, Moilanen K, Rantakallio P, Veijola J, Oja H, et al. Early developmental milestones in adult schizophrenia and other psychoses. A 31-year follow-up of the Northern Finland 1966 birth cohort. Schizophr Res 2001;52:1-9.  Back to cited text no. 26
Ornoy A, Ratzon N, Greenbaum C, Peretz E, Soriano D, Dulitzky M, et al. Neurobehaviour of school age children born to diabetic mothers. Arch Dis Child Fetal Neonatal Ed 1998;79:F94-9.  Back to cited text no. 27
Yamashita Y, Kawano Y, Kuriya N, Murakami Y, Matsuishi T, Yoshimatsu K, et al. Intellectual development of offspring of diabetic mothers. Acta Paediatr 1996;85:1192-6.  Back to cited text no. 28
Haghir H, Rezaee AA, Nomani H, Sankian M, Kheradmand H, Hami J, et al. Sexual dimorphism in expression of insulin and insulin-like growth factor-I receptors in developing rat cerebellum. Cell Mol Neurobiol 2013;33:369-77.  Back to cited text no. 29
Hami J, Kerachian MA, Karimi R, Haghir H, Sadr-Nabavi A. Effects of streptozotocin-induced type 1 maternal diabetes on PI3K/AKT signaling pathway in the hippocampus of rat neonates. J Recept Signal Transduct Res 2016;36:254-60.  Back to cited text no. 30
Hami J, Sadr-Nabavi A, Sankian M, Balali-Mood M, Haghir H. The effects of maternal diabetes on expression of insulin-like growth factor-1 and insulin receptors in male developing rat hippocampus. Brain Struct Funct 2013;218:73-84.  Back to cited text no. 31
Hami J, Vafaei-Nezhad S, Ghaemi K, Sadeghi A, Ivar G, Shojae F, et al. Stereological study of the effects of maternal diabetes on cerebellar cortex development in rat. Metab Brain Dis 2016;31:643-52.  Back to cited text no. 32
Khaksar Z, Jelodar G, Hematian H. Effect of maternal diabetes on cerebellum histomorphometry in neonatal rats. J Shahid Sadoughi Univ Med Sci 2010;18:56-63.  Back to cited text no. 33
Suzuki N, Svensson K, Eriksson UJ. High glucose concentration inhibits migration of rat cranial neural crest cells in vitro. Diabetologia 1996;39:401-11.  Back to cited text no. 34
Petzoldt AG, Sigrist SJ. Synaptogenesis. Curr Biol 2014;24:R1076-80.  Back to cited text no. 35
Yamaguchi Y. Glycobiology of the synapse: The role of glycans in the formation, maturation, and modulation of synapses. Biochim Biophys Acta 2002;1573:369-76.  Back to cited text no. 36
Sanes J, Jessell T. The formation and regeneration of synapses. Princ Neural Sci 2000;4:1087-114.  Back to cited text no. 37
Poon VY, Choi S, Park M. Growth factors in synaptic function. Front Synaptic Neurosci 2013;5:1-18.  Back to cited text no. 38
Bhattacharya B, Sarkar PK. Tubulin gene expression during synaptogenesis in rat, mouse and chick brain. Int J Dev Neurosci 1991;9:89-99.  Back to cited text no. 39
Huttenlocher PR, Dabholkar AS. Regional differences in synaptogenesis in human cerebral cortex. J Comp Neurol 1997;387:167-78.  Back to cited text no. 40
Stiles J, Jernigan TL. The basics of brain development. Neuropsychol Rev 2010;20:327-48.  Back to cited text no. 41
Lin HM, Liu CY, Jow GM, Tang CY. Toluene disrupts synaptogenesis in cultured hippocampal neurons. Toxicol Lett 2009;184:90-6.  Back to cited text no. 42
Benson DL, Colman DR, Huntley GW. Molecules, maps and synapse specificity. Nat Rev Neurosci 2001;2:899-909.  Back to cited text no. 43
Oppenheim RW, Foelix RF. Synaptogenesis in the chick embryo spinal cord. Nat New Biol 1972;235:126-8.  Back to cited text no. 44
Sokoloff L, Kennedy C. In: The action of thyroid hormones and their influence on brain development and function. Biology of Brain Dysfunction. Vol. 2. Plenum, New York; 1973. p. 295-332.  Back to cited text no. 45
Cohen-Cory S. The developing synapse: Construction and modulation of synaptic structures and circuits. Science 2002;298:770-6.  Back to cited text no. 46
Vicario-Abejón C, Owens D, McKay R, Segal M. Role of neurotrophins in central synapse formation and stabilization. Nat Rev Neurosci 2002;3:965-74.  Back to cited text no. 47
Panzer JA, Gibbs SM, Dosch R, Wagner D, Mullins MC, Granato M, et al. Neuromuscular synaptogenesis in wild-type and mutant zebrafish. Dev Biol 2005;285:340-57.  Back to cited text no. 48
Garner CC, Shen K. Structure and function of vertebrate and invertebrate active zones. In: Ehlers M, Hell J, editors. Structural and functional organization of the synapse. New York: Springer; 2008. P.63-89.  Back to cited text no. 49
Schoch S, Gundelfinger ED. Molecular organization of the presynaptic active zone. Cell Tissue Res 2006;326:379-91.  Back to cited text no. 50
Montgomery JM, Zamorano PL, Garner CC. MAGUKs in synapse assembly and function: An emerging view. Cell Mol Life Sci 2004;61:911-29.  Back to cited text no. 51
Garner CC, Zhai RG, Gundelfinger ED, Ziv NE. Molecular mechanisms of CNS synaptogenesis. Trends Neurosci 2002;25:243-51.  Back to cited text no. 52
Waites CL, Craig AM, Garner CC. Mechanisms of vertebrate synaptogenesis. Annu Rev Neurosci 2005;28:251-74.  Back to cited text no. 53
Suzuki T, Yao W. Molecular and structural bases for postsynaptic signal processing: Interaction between postsynaptic density and postsynaptic membrane rafts. J Neurorestoratol 2014;2:1-14.  Back to cited text no. 54
Lu CS, Van Vactor D. Genetic analysis of synaptogenesis. In: Rakic JL, editor. Cellular Migration and Formation of Neuronal Connections. Oxford: Academic Press; 2013. p. 537-77.  Back to cited text no. 55
Chua JJ, Kindler S, Boyken J, Jahn R. The architecture of an excitatory synapse. J Cell Sci 2010;123:819-23.  Back to cited text no. 56
Davletov B, Montecucco C. Lipid function at synapses. Curr Opin Neurobiol 2010;20:543-9.  Back to cited text no. 57
Dityatev A, El-Husseini A, editors. Molecular mechanisms of synaptogenesis. New York: Springer Science and Business Media LLC; 2006.  Back to cited text no. 58
Gincel D, Shoshan-Barmatz V. The synaptic vesicle protein synaptophysin: Purification and characterization of its channel activity. Biophys J 2002;83:3223-9.  Back to cited text no. 59
Arthur CP, Stowell MH. Structure of synaptophysin: A hexameric MARVEL-domain channel protein. Structure 2007;15:707-14.  Back to cited text no. 60
Jahn R, Schiebler W, Ouimet C, Greengard P. A 38,000-dalton membrane protein (p38) present in synaptic vesicles. Proc Natl Acad Sci 1985;82:4137-41.  Back to cited text no. 61
Davies HA, Kelly A, Dhanrajan TM, Lynch MA, Rodríguez JJ, Stewart MG, et al. Synaptophysin immunogold labelling of synapses decreases in dentate gyrus of the hippocampus of aged rats. Brain Res 2003;986:191-5.  Back to cited text no. 62
Edelmann L, Hanson PI, Chapman ER, Jahn R. Synaptobrevin binding to synaptophysin: A potential mechanism for controlling the exocytotic fusion machine. EMBO J 1995;14:224-31.  Back to cited text no. 63
McMahon HT, Bolshakov VY, Janz R, Hammer RE, Siegelbaum SA, Südhof TC, et al. Synaptophysin, a major synaptic vesicle protein, is not essential for neurotransmitter release. Proc Natl Acad Sci U S A 1996;93:4760-4.  Back to cited text no. 64
Eshkind LG, Leube RE. Mice lacking synaptophysin reproduce and form typical synaptic vesicles. Cell Tissue Res 1995;282:423-33.  Back to cited text no. 65
Janz R, Südhof TC, Hammer RE, Unni V, Siegelbaum SA, Bolshakov VY, et al. Essential roles in synaptic plasticity for synaptogyrin I and synaptophysin I. Neuron 1999;24:687-700.  Back to cited text no. 66
Fletcher TL, Cameron P, De Camilli P, Banker G. The distribution of synapsin I and synaptophysin in hippocampal neurons developing in culture. J Neurosci 1991;11:1617-26.  Back to cited text no. 67
Knaus P, Marquèze-Pouey B, Scherer H, Betz H. Synaptoporin, a novel putative channel protein of synaptic vesicles. Neuron 1990;5:453-62.  Back to cited text no. 68
Alladi PA, Wadhwa S, Singh N. Effect of prenatal auditory enrichment on developmental expression of synaptophysin and syntaxin 1 in chick brainstem auditory nuclei. Neuroscience 2002;114:577-90.  Back to cited text no. 69
Elibol-Can B, Kilic E, Yuruker S, Jakubowska-Dogru E. Investigation into the effects of prenatal alcohol exposure on postnatal spine development and expression of synaptophysin and PSD95 in rat hippocampus. Int J Dev Neurosci 2014;33:106-14.  Back to cited text no. 70
Pyeon HJ, Lee YI. Differential expression levels of synaptophysin through developmental stages in hippocampal region of mouse brain. Anat Cell Biol 2012;45:97-102.  Back to cited text no. 71
Li L, Tasic B, Micheva KD, Ivanov VM, Spletter ML, Smith SJ, et al. Visualizing the distribution of synapses from individual neurons in the mouse brain. PLoS One 2010;5:e11503.  Back to cited text no. 72
Leclerc N, Beesley PW, Brown I, Colonnier M, Gurd JW, Paladino T, et al. Synaptophysin expression during synaptogenesis in the rat cerebellar cortex. J Comp Neurol 1989;280:197-212.  Back to cited text no. 73
Marazzi G, Buckley KM. Accumulation of mRNAs encoding synaptic vesicle-specific proteins precedes neurite extension during early neuronal development. Dev Dyn 1993;197:115-24.  Back to cited text no. 74
Fagnou DD, Tuchek JM. The biochemistry of learning and memory. Mol Cell Biochem 1995;149-150:279-86.  Back to cited text no. 75
Frick KM, Fernandez SM. Enrichment enhances spatial memory and increases synaptophysin levels in aged female mice. Neurobiol Aging 2003;24:615-26.  Back to cited text no. 76
Frick KM, Fernandez SM, Bulinski SC. Estrogen replacement improves spatial reference memory and increases hippocampal synaptophysin in aged female mice. Neuroscience 2002;115:547-58.  Back to cited text no. 77
Zhan SS, Beyreuther K, Schmitt HP. Quantitative assessment of the synaptophysin immuno-reactivity of the cortical neuropil in various neurodegenerative disorders with dementia. Dementia 1993;4:66-74.  Back to cited text no. 78
Chambers JS, Thomas D, Saland L, Neve RL, Perrone-Bizzozero NI. Growth-associated protein 43 (GAP-43) and synaptophysin alterations in the dentate gyrus of patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:283-90.  Back to cited text no. 79
Eastwood SL, Burnet PW, Harrison PJ. Altered synaptophysin expression as a marker of synaptic pathology in schizophrenia. Neuroscience 1995;66:309-19.  Back to cited text no. 80
McGahon B, Clements MP, Lynch MA. The ability of aged rats to sustain long-term potentiation is restored when the age-related decrease in membrane arachidonic acid concentration is reversed. Neuroscience 1997;81:9-16.  Back to cited text no. 81
Thome J, Pesold B, Baader M, Hu M, Gewirtz JC, Duman RS, et al. Stress differentially regulates synaptophysin and synaptotagmin expression in hippocampus. Biol Psychiatry 2001;50:809-12.  Back to cited text no. 82
Hans J, Lammens M, Wesseling P, Hori A. Development and developmental disorders of the human cerebellum. In: Clinical Neuroembryology. Berlin, Heidelberg: Springer; 2014. p. 371-420.  Back to cited text no. 83
Voogd J, Jaarsma D, Marani E. The cerebellum: chemoarchitecture and anatomy. In: Swanson LW, Bjöorklund A, Hökfelt T, editors. Handbook of Chemical Neuroanatomy. Vol. 12. Amsterdam, Elsevier; 1996. p. 1-369.  Back to cited text no. 84
Hibi M, Shimizu T. Development of the cerebellum and cerebellar neural circuits. Dev Neurobiol 2012;72:282-301.  Back to cited text no. 85
Brooks VB. Comment: On functions of the “cerebellar circuit” in movement control. Can J Physiol Pharmacol 1981;59:776-8.  Back to cited text no. 86
Beaton A, Mariën P. Language, cognition and the cerebellum: Grappling with an enigma. Cortex 2010;46:811-20.  Back to cited text no. 87
Allen G, Buxton RB, Wong EC, Courchesne E. Attentional activation of the cerebellum independent of motor involvement. Science 1997;275:1940-3.  Back to cited text no. 88
Butts T, Green MJ, Wingate RJ. Development of the cerebellum: Simple steps to make a 'little brain'. Development 2014;141:4031-41.  Back to cited text no. 89
Altman J, Bayer S. Development of the Cerebellar System: In Relation to its Evolution, Structure, and Functions. Boca Raton, FL: CRC; 1997.  Back to cited text no. 90
Goldowitz D, Hamre K. The cells and molecules that make a cerebellum. Trends Neurosci 1998;21:375-82.  Back to cited text no. 91
Hatten ME, Heintz N. Mechanisms of neural patterning and specification in the developing cerebellum. Annu Rev Neurosci 1995;18:385-408.  Back to cited text no. 92
Hatten ME, Alder J, Zimmerman K, Heintz N. Genes involved in cerebellar cell specification and differentiation. Curr Opin Neurobiol 1997;7:40-7.  Back to cited text no. 93
Millen KJ, Millonig JH, Wingate RJ, Alder J, Hatten ME. Neurogenetics of the cerebellar system. J Child Neurol 1999;14:574-81.  Back to cited text no. 94
Wang VY, Zoghbi HY. Genetic regulation of cerebellar development. Nat Rev Neurosci 2001;2:484-91.  Back to cited text no. 95
Altman J. Postnatal development of the cerebellar cortex in the rat. I. The external germinal layer and the transitional molecular layer. J Comp Neurol 1972;145:353-97.  Back to cited text no. 96
Altman J, Winfree AT. Postnatal development of the cerebellar cortex in the rat. V. Spatial organization of Purkinje cell perikarya. J Comp Neurol 1977;171:1-6.  Back to cited text no. 97
Allen VM, Armson BA, Wilson RD, Allen VM, Blight C, Gagnon A, et al. Teratogenicity associated with pre-existing and gestational diabetes. J Obstet Gynaecol Can 2007;29:927-44.  Back to cited text no. 98
Anderson JL, Waller DK, Canfield MA, Shaw GM, Watkins ML, Werler MM, et al. Maternal obesity, gestational diabetes, and central nervous system birth defects. Epidemiology 2005;16:87-92.  Back to cited text no. 99
Eriksson UJ. Congenital anomalies in diabetic pregnancy. Seminars in Fetal and Neonatal Med 2009;14:85-93.  Back to cited text no. 100
Farooq M, Ayaz A, Bahoo A, Ahmad I. Maternal and neonatal outcomes in gestational diabetes mellitus. Int J Endocrinol Metabol 2007;2007:109-15.  Back to cited text no. 101
Baydas G, Nedzvetskii VS, Nerush PA, Kirichenko SV, Yoldas T. Altered expression of NCAM in hippocampus and cortex may underlie memory and learning deficits in rats with streptozotocin-induced diabetes mellitus. Life Sci 2003;73:1907-16.  Back to cited text no. 102
Popoviç M, Biessels GJ, Isaacson RL, Gispen WH. Learning and memory in streptozotocin-induced diabetic rats in a novel spatial/object discrimination task. Behav Brain Res 2001;122:201-7.  Back to cited text no. 103
Rizzo T, Metzger BE, Burns WJ, Burns K. Correlations between antepartum maternal metabolism and intelligence of offspring. N Engl J Med 1991;325:911-6.  Back to cited text no. 104
Ramanathan M, Jaiswal AK, Bhattacharya SK. Hyperglycaemia in pregnancy: Effects on the offspring behaviour with special reference to anxiety paradigms. Indian J Exp Biol 2000;38:231-6.  Back to cited text no. 105
Freinkel N. Banting lecture 1980: Of pregnancy and progeny. Diabetes 1980;29:1023-35.  Back to cited text no. 106
Sells CJ, Robinson NM, Brown Z, Knopp RH. Long-term developmental follow-up of infants of diabetic mothers. J Pediatr 1994;125:S9-17.  Back to cited text no. 107
Ornoy A, Ratzon N, Greenbaum C, Wolf A, Dulitzky M. School-age children born to diabetic mothers and to mothers with gestational diabetes exhibit a high rate of inattention and fine and gross motor impairment. J Pediatr Endocrinol Metab 2001;14 Suppl 1:681-9.  Back to cited text no. 108
Sze CI, Troncoso JC, Kawas C, Mouton P, Price DL, Martin LJ, et al. Loss of the presynaptic vesicle protein synaptophysin in hippocampus correlates with cognitive decline in Alzheimer disease. J Neuropathol Exp Neurol 1997;56:933-44.  Back to cited text no. 109
Shin BC, Fujikura K, Suzuki T, Tanaka S, Takata K. Glucose transporter GLUT3 in the rat placental barrier: A possible machinery for the transplacental transfer of glucose. Endocrinology 1997;138:3997-4004.  Back to cited text no. 110
Takata K, Fujikura K, Shin BC. Ultrastructure of the rodent placental labyrinth: A Site of barrier and transport. J Reprod Dev 1997;43:13-24.  Back to cited text no. 111
Aerts L, van Assche FA. Rat foetal endocrine pancreas in experimental diabetes. J Endocrinol 1977;73:339-46.  Back to cited text no. 112
Eriksson UJ, Simán CM. Pregnant diabetic rats fed the antioxidant butylated hydroxytoluene show decreased occurrence of malformations in offspring. Diabetes 1996;45:1497-502.  Back to cited text no. 113
Simán CM, Eriksson UJ. Vitamin C supplementation of the maternal diet reduces the rate of malformation in the offspring of diabetic rats. Diabetologia 1997;40:1416-24.  Back to cited text no. 114
Simán CM, Eriksson UJ. Vitamin E decreases the occurrence of malformations in the offspring of diabetic rats. Diabetes 1997;46:1054-61.  Back to cited text no. 115
Wentzel P, Thunberg L, Eriksson UJ. Teratogenic effect of diabetic serum is prevented by supplementation of superoxide dismutase and N-acetylcysteine in rat embryo culture. Diabetologia 1997;40:7-14.  Back to cited text no. 116


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