Valproic Acid Exposure during Early Postnatal Gliogenesis Leads to Autistic-like Behaviors in Rats

다국어 초록 (Multilingual Abstract)

Objective: We reported that postnatal exposure of rats to valproic acid (VPA) stimulated proliferation of glial precursors during cortical gliogenesis. However, there are no reports whether enhanced postnatal gliogenesis affects behaviors related to neuropsychiatric disorders.
Methods: After VPA treatment during the postnatal day (PND) 2 to PND 4, four behavioral test, such as open field locomotor test, elevated plus maze test, three-chamber social interaction test, and passive avoidance test, were performed at PND 21 or 22.
Results: VPA treated rats showed significant hyperactive behavior in the open field locomotor test (p＜0.05). Moreover, the velocity of movement in the VPA group was increased by 69.5% (p＜0.01). In the elevated plus maze test, VPA exposed rats expressed significantly lower percentage of time spent on and of entries into open arms more than the control group (p＜0.05).
Also, both sociability and social preference indices with strangers in the three-chamber social interaction test were significantly lower in the VPA exposed rats (p＜0.05).
Conclusion: Our results suggest that altered glial cell development is another locus at which pathogenetic factors can operate to contribute to the neurodevelopmental disorder.

참고문헌 (Reference)

1 Hee Jae Lee, "Valproic acid stimulates proliferation of glial precursors during cortical gliogenesis in developing rat" Wiley-Blackwell 76 (76): 780-798, 2016

2 Kumamaru E, "Valproic acid selectively suppresses the formation of inhibitory synapses in cultured cortical neurons" 569 : 142-147, 2014

3 Ornoy A, "Valproic acid in pregnancy: how much are we endangering the embryo and fetus?" 28 : 1-10, 2009

4 Lovell BV, "Valproate semisodium ER for migraine and cluster headache prophylaxis" 6 : 495-504, 2010

5 Yochum CL, "VPA-induced apoptosis and behavioral deficits in neonatal mice" 1203 : 126-132, 2008

6 Araque A, "Tripartite synapses: glia, the unacknowledged partner" 22 : 208-215, 1999

7 Arndt TL, "The teratology of autism" 23 : 189-199, 2005

8 Kim KC, "The critical period of valproate exposure to induce autistic symptoms in Sprague-Dawley rats" 201 : 137-142, 2011

9 Wang DD, "The astrocyte odyssey" 86 : 342-367, 2008

10 Mackey C, "The anticonvulsants market" 9 : 265-266, 2010

11 Kim JW, "Subchronic treatment of donepezil rescues impaired social, hyperactive, and stereotypic behavior in valproic acid-induced animal model of autism" 9 : e104927-, 2014

12 Reynolds S, "Sensory and motor characterization in the postnatal valproate rat model of autism" 34 : 258-267, 2012

13 Pfrieger FW, "Roles of glial cells in synapse development" 66 : 2037-2047, 2009

14 Parpura V, "Physiological astrocytic calcium levels stimulate glutamate release to modulate adjacent neurons" 97 : 8629-8634, 2000

15 Kim KC, "Pax6-dependent cortical glutamatergic neuronal differentiation regulates autism-like behavior in prenatally valproic acid-exposed rat offspring" 49 : 512-528, 2014

16 Chauhan A, "Oxidative stress in autism" 13 : 171-181, 2006

17 Sloan SA, "Mechanisms of astrocyte development and their contributions to neurodevelopmental disorders" 27 : 75-81, 2014

18 Miyazaki K, "Maternal administration of thalidomide or valproic acid causes abnormal serotonergic neurons in the offspring: implication for pathogenesis of autism" 23 : 287-297, 2005

19 Koren G, "Major malformations with valproic acid" 52 : 441-442, 2006

20 Stodgell CJ, "Induction of the homeotic gene Hoxa1 through valproic acid's teratogenic mechanism of action" 28 : 617-624, 2006

21 Rajkowska G, "Gliogenesis and glial pathology in depression" 6 : 219-233, 2007

22 Laurence JA, "Glial fibrillary acidic protein is elevated in superior frontal, parietal and cerebellar cortices of autistic subjects" 4 : 206-210, 2005

23 Fatemi SH, "Expression of astrocytic markers aquaporin 4 and connexin 43 is altered in brains of subjects with autism" 62 : 501-507, 2008

24 Darine Froy N. Mabunga, "Exploring the Validity of Valproic Acid Animal Model of Autism" 한국뇌신경과학회 24 (24): 285-300, 2015

25 Clarke LE, "Emerging roles of astrocytes in neural circuit development" 14 : 311-321, 2013

26 Bond DJ, "Divalproex sodium versus placebo in the treatment of acute bipolar depression: a systematic review and meta-analysis" 124 : 228-234, 2010

27 Nedergaard M, "Direct signaling from astrocytes to neurons in cultures of mammalian brain cells" 263 : 1768-1771, 1994

28 Söğüt S, "Changes in nitric oxide levels and antioxidant enzyme activities may have a role in the pathophysiological mechanisms involved in autism" 331 : 111-117, 2003

29 Schneider T, "Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism" 30 : 80-89, 2005

30 Molofsky AV, "Astrocytes and disease: a neurodevelopmental perspective" 26 : 891-907, 2012

31 Allen NJ, "Astrocyte regulation of synaptic behavior" 30 : 439-463, 2014

32 Al-Amin MM, "Astaxanthin improves behavioral disorder and oxidative stress in prenatal valproic acid-induced mice model of autism" 286 : 112-121, 2015

33 Pellow S, "Anxiolytic and anxiogenic drug effects on exploratory activity in an elevated plus-maze: a novel test of anxiety in the rat" 24 : 525-529, 1986

34 Bambini-Junior V, "Animal model of autism induced by prenatal exposure to valproate: behavioral changes and liver parameters" 1408 : 8-16, 2011

35 Pragnya B, "Ameliorating effect of piperine on behavioral abnormalities and oxidative markers in sodium valproate induced autism in BALB/C mice" 270 : 86-94, 2014

36 Chomiak T, "Altering the trajectory of early postnatal cortical development can lead to structural and behavioural features of autism" 11 : 102-, 2010

37 Cao F, "Alteration of astrocytes and Wnt/β-catenin signaling in the frontal cortex of autistic subjects" 9 : 223-, 2012

38 Wagner GC, "A new neurobehavioral model of autism in mice: pre- and postnatal exposure to sodium valproate" 36 : 779-793, 2006