A Critical Period in Purkinje Cell Development Is Mediated by Local Estradiol Synthesis, Disrupted by Inflammation, and Has Enduring Consequences Only for Males.
Identifying and understanding critical periods in brain development is essential to decoding the long-term impact of widespread, poorly defined, and frequently occurring insults such as inflammation. Using the laboratory rat Rattus norvegicus, we have discovered a narrowly constrained critical period in Purkinje neuron development subject to dysregulation by inflammation. The onset and offset of heightened vulnerability are attributed to a tightly orchestrated gene expression profile present only during the second postnatal week and not the first or third weeks. Genes expressed during this time code for enzymes and receptors which are critical not only for prostaglandin production and activity but also for estradiol production via the aromatase enzyme and estradiol action via the α isoform of the estrogen receptor. The two synthetic pathways are connected by prostaglandin E2 (PGE2) activation of the aromatase enzyme, as we reported previously (Dean et al., 2012b) and confirm here. Dysregulation of the PGE2-estradiol pathway during the second week by treatment with PGE2 or lipopolysaccharides produces enduring consequences as a result of reduced growth of Purkinje dendritic trees and impaired juvenile social play behavior, but only in males. The deleterious consequences of inflammation locally in the cerebellum are prevented by peripheral treatment with the cyclooxygenase inhibitor nimesulide or the aromatase inhibitor formestane. These findings highlight a novel regulatory pathway that creates a critical period in brain development vulnerable to dysregulation by inflammation.



The cerebellum is increasingly appreciated for its role in social, emotional, and cognitive behaviors. It is consistently and severely affected in neuropsychiatric disorders originating during development, such as autism spectrum disorder and schizophrenia. We have identified a critical period in rat development during the second week of life that is dysregulated by inflammatory insults. An intrinsic program of gene expression determines the critical period. The enduring consequences of inflammation during the second postnatal week are stunted dendrites of the cerebellum's principal neurons, Purkinje cells, and impairments in later social behavior. These changes are not evident if inflammation occurs during the first or third week, highlighting the importance of fine-grained analyses of developmental processes and the factors that influence them.
Program in Neuroscience and Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland 21201.
Jessica F
0000-0003-1858-8394
JF
Hoffman
Program in Neuroscience and Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland 21201 cwrig003@umaryland.edu.
Christopher L
0000-0002-3413-394X
CL
Wright
Program in Neuroscience and Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland 21201.
Margaret M
0000-0003-2243-4726
MM
McCarthy
D000375:Aging / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D049108:Cell Enlargement; D003423:Critical Period, Psychological; D003712:Dendrites / Q000378:metabolism / Q000473:pathology; D004958:Estradiol / Q000096:biosynthesis*; D018507:Gene Expression Regulation, Developmental; D007249:Inflammation / Q000503:physiopathology*; D008297:Male; D055495:Neurogenesis; D011689:Purkinje Cells / Q000378:metabolism* / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004958:Estradiol
Purkinje cell; cerebellum; estradiol; inflammation; prostaglandin; social play
Brain Res. 1987 Sep 29;422(1):52-62
2890418
Mol Psychiatry. 2014 Feb;19(2):259-64
23337946
Dev Med Child Neurol. 2001 Oct;43(10):685-91
11665825
Biol Psychiatry. 2008 Jul 15;64(2):81-8
18395701
J Neurosci. 2002 Oct 1;22(19):8586-96
12351732
Nature. 1998 Jan 15;391(6664):281-5
9440691
Science. 2011 Nov 11;334(6057):809-13
22021672
Horm Behav. 1981 Jun;15(2):197-213
7250910
Endocrinology. 2011 Jan;152(1):223-35
21068160
J Reprod Med. 1994 Apr;39(4):257-61
8040841
Exp Neurol. 2009 May;217(1):63-73
19416671
Mol Psychiatry. 2015 Feb;20(1):118-25
25199916
Nat Commun. 2014 Dec 10;5:5748
25494366
Prostaglandins Other Lipid Mediat. 2005 May;76(1-4):1-18
15967158
J Neurosci. 2007 Oct 3;27(40):10832-9
17913916
Eur J Neurosci. 2012 Apr;35(8):1218-29
22512254
Pediatrics. 2001 May;107(5):E84
11331734
Nat Neurosci. 2004 Jun;7(6):643-50
15156148
Cortex. 2010 Jul-Aug;46(7):831-44
20152963
Dev Neurobiol. 2012 Mar;72(3):282-301
21309081
J Physiol. 2001 Sep 1;535(Pt 2):445-72
11533136
Neuron. 2007 Oct 25;56(2):399-413
17964254
Synapse. 2010 Nov;64(11):801-7
20842717
Brain. 2000 May;123 ( Pt 5):1041-50
10775548
Endocrinology. 2012 Nov;153(11):5415-27
23054057
Nat Rev Neurosci. 2001 Jul;2(7):484-91
11433373
Brain. 2007 Oct;130(Pt 10):2646-60
17872929
Neuroendocrinology. 2011;93(4):230-40
21325792
Biochim Biophys Acta. 2006 Aug;1766(1):104-19
16859832
Biol Sex Differ. 2015 Sep 10;6:16
26361539
Front Neurosci. 2015 Nov 06;9:420
26594141
Brain. 2000 May;123 ( Pt 5):1051-61
10775549
Brain. 2001 Jan;124(Pt 1):60-6
11133787
Brain. 1998 Apr;121 ( Pt 4):561-79
9577385
Brain Res. 1989 Jan 9;476(2):307-16
2702471
Endocrinology. 2003 Oct;144(10):4466-77
12960093
Physiol Rev. 2008 Jan;88(1):91-124
18195084
Nature. 2010 Nov 11;468(7321):232-43
21068832
J Neurosci. 2009 Oct 21;29(42):13274-82
19846715
Front Neuroendocrinol. 2012 Oct;33(4):403-11
22975197
J Neurosci. 2000 Jul 1;20(13):4954-61
10864953
Annu Rev Neurosci. 2009;32:413-34
19555291
Nature. 2012 Aug 30;488(7413):647-51
22763451
Mol Psychiatry. 2015 Apr;20(4):440-6
24934179
J Comp Neurol. 2001 Feb 12;430(3):396-409
11169476
J Comp Neurol. 1972 Aug;145(4):399-463
5044254
J Neurosci. 2012 Mar 21;32(12):4319-29
22442093
Brain Behav Immun. 2012 Mar;26(3):393
22001185
Clin Endocrinol (Oxf). 1998 Mar;48(3):325-9
9578823
Arch Pediatr Adolesc Med. 2010 May;164(5):470-7
20439799
Cerebellum. 2012 Jun;11(2):416-7
22198873
J Neurophysiol. 2011 Nov;106(5):2322-45
21795627
J Neurosci. 1997 Dec 1;17(23):9145-56
9364061