[Frontiers In Bioscience, Landmark, 23, 1465-1486, March 1, 2018]

Up states-based developmental trajectories of the autistic cerebral cortex

Pavlos Rigas1

1Neurophysiology Lab, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece


1. Abstract
2. Introduction
3. Up and Down states of the cerebral cortex
3.1. Up and Down cortical states in vitro
3.2. The significance of Up and Down cortical states
4. The endophenotype
4.1. Spike and Wave Discharges: an endophenotype of epilepsy
4.1.1. Comparing ictogenesis in the cortex and studying mechanisms of epileptic activity
4.1.2. Screening for new antiepileptic drugs
5. Using spontaneous cortical Up and Down states to define critical periods for the development of autism
5.1. The Fmr1KO rodent model of autism
5.2. The developmental delay and heterochronicity of autism
5.3. Proposing a scheme for the neurobiological research of autism onset
5.3.1. Why record in vitro?
5.3.2. Why record in the interface chamber?The interface vs the submerged chamber The submerged chamber pertains to intracellular rather than extracellular recordings Space limitations of the submerged chamber
5.3.3. Why developmental trajectories?
5.3.4. The choice of ages
5.3.5. The choice of cortices
6. Conclusions
7. Acknowledgments
8. References


Autism is a severe neurodevelopmental disorder which affects information processing in the brain as the result of an abnormally developed cortex, brought about in ways that are poorly understood. The disorder is characterized by a very early onset, however, neurobiological studies at such young ages are often precluded in humans, thus, rendering respective research in appropriate animal models of the disease invaluable. The bulk of this research has focused mainly on how experimental models differ from normal rather than on when they begin to differ. However, understanding the neurobiology of autism at its onset is important for both describing and treating the disorder. Moreover, modelling human behaviours in animals is often very difficult. Therefore, in order for neurobiological research of autism to proceed it is essential to “decompose” the disorder into simpler, behavior-independent biological parameters. Here, I propose how network dynamics of local microcircuits may serve such a role in order to derive developmental trajectories of the cerebral cortex that will allow us to detect and investigate the disorder at its very beginning.


1. KC Ess: The neurobiology of tuberous sclerosis complex. Semin Pediatr Neurol 13, 37-42 (2006)
DOI: 10.1016/j.spen.2006.01.009

2. R Guerrini, R Carrozzo, R Rinaldi, and P Bonanni: Angelman syndrome: etiology, clinical features, diagnosis, and management of symptoms. Paediatr Drugs 5, 647-61 (2003)
DOI: 10.2165/00148581-200305100-00001

3. RJ Hagerman, E Berry-Kravis, WE Kaufmann, MY Ono, N Tartaglia, A Lachiewicz, R Kronk, C Delahunty, D Hessl, J Visootsak, J Picker, L Gane, and M Tranfaglia: Advances in the treatment of fragile X syndrome. Pediatrics 123, 378-90 (2009)
DOI: 10.1542/peds.2008-0317

4. GL Wiesner, SB Cassidy, SJ Grimes, AL Matthews, and LS Acheson: Clinical consult: developmental delay/fragile X syndrome. Prim Care 31, 621-5, x (2004)

5. E Fombonne: Epidemiology of autistic disorder and other pervasive developmental disorders. J Clin Psychiatry 66 Suppl 10, 3-8 (2005)

6. ML Ganz: The lifetime distribution of the incremental societal costs of autism. Arch Pediatr Adolesc Med 161, 343–349 (2007)
DOI: 10.1001/archpedi.161.4.343

7. MD Kogan, SJ Blumberg, LA Schieve, CA Boyle, JM Perrin, RM Ghandour, GK Singh, BB Strickland, E Trevathan, and PC van Dyck: Prevalence of parent-reported diagnosis of autism spectrum disorder among children in the US, 2007. Pediatrics 124, 1395-403 (2009)
DOI: 10.1542/peds.2009-1522

8. JP Leigh and J Du: Brief Report: Forecasting the Economic Burden of Autism in 2015 and 2025 in the United States. J Autism Dev Disord 45, 4135-9 (2015)
DOI: 10.1007/s10803-015-2521-7

9. ML Ganz: The lifetime distribution of the incremental societal costs of autism. Arch Pediatr Adolesc Med 161, 343-9 (2007)
DOI: 10.1001/archpedi.161.4.343

10. R Landa and E Garrett-Mayer: Development in infants with autism spectrum disorders: a prospective study. J Child Psychol Psychiatry 47, 629–638 (2006)
DOI: 10.1111/j.1469-7610.2006.01531.x

11. AM Wetherby, J Woods, L Allen, J Cleary, H Dickinson, and C Lord: Early indicators of autism spectrum disorders in the second year of life. J Autism Dev Disord 34, 473–493 (2004)
DOI: 10.1007/s10803-004-2544-y

12. L Zwaigenbaum, S Bryson, T Rogers, W Roberts, J Brian, and P Szatmari: Behavioral manifestations of autism in the first year of life. Int J Dev Neurosci 23, 143–152 (2005)
DOI: 10.1016/j.ijdevneu.2004.05.001

13. G Dawson: Early behavioral intervention, brain plasticity, and the prevention of autism spectrum disorder. Developm Psychopathol 20, 775–803 (2008)
DOI: 10.1017/S0954579408000370

14. M Helt, E Kelley, M Kinsbourne, J Pandey, H Boorstein, Μ Herbert, and D Fein: Can children with autism recover? If so, how? Νeuropsychol Rev 18, 339–366 (2008)

15. E Courchesne, K Pierce, CM Schumann, E Redcay, JA Buckwalter, DP Kennedy, and J Morgan: Mapping early brain development in autism. Neuron 56, 399-413 (2007)
DOI: 10.1016/j.neuron.2007.10.016

16. P Penzes, ME Cahill, KA Jones, JE VanLeeuwen, and KM Woolfrey: Dendritic spine pathology in neuropsychiatric disorders. Nat Neurosci 14, 285-93 (2011)
DOI: 10.1038/nn.2741

17. LD Selemon and PS Goldman-Rakic: The reduced neuropil hypothesis: a circuit based model of schizophrenia. Biol Psychiatry 45, 17-25 (1999)
DOI: 10.1016/S0006-3223(98)00281-9

18. JJ Hutsler and H Zhang: Increased dendritic spine densities on cortical projection neurons in autism spectrum disorders. Brain Res 1309, 83-94 (2010)
DOI: 10.1016/j.brainres.2009.09.120

19. LA Glantz and DA Lewis: Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch Gen Psychiatry 57, 65-73 (2000)
DOI: 10.1001/archpsyc.57.1.65

20. C Tackenberg, A Ghori, and R Brandt: Thin, stubby or mushroom: spine pathology in Alzheimer’s disease. Curr Alzheimer Res 6, 261-8 (2009)
DOI: 10.2174/156720509788486554

21. P Penzes, A Buonanno, M Passafaro, C Sala, and RA Sweet: Developmental vulnerability of synapses and circuits associated with neuropsychiatric disorders. J Neurochem 126, 165-82 (2013)
DOI: 10.1111/jnc.12261

22. DD Krueger and MF Bear: Toward fulfilling the promise of molecular medicine in fragile X syndrome. Annu Rev Med 62, 411-29 (2011)
DOI: 10.1146/annurev-med-061109-134644

23. II Gottesman and TD Gould: The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 160, 636-45 (2003)
DOI: 10.1176/appi.ajp.160.4.636

24. II Gottesman and J Shields: Genetic theorizing and schizophrenia. Br J Psychiatry 122, 15-30 (1973)
DOI: 10.1192/bjp.122.1.15

25. TD Gould and II Gottesman: Psychiatric endophenotypes and the development of valid animal models. Genes Brain Behav 5, 113-9 (2006)
DOI: 10.1111/j.1601-183X.2005.00186.x

26. G Hasler, WC Drevets, HK Manji, and DS Charney: Discovering endophenotypes for major depression. Neuropsychopharmacology 29, 1765-81 (2004)
DOI: 10.1038/sj.npp.1300506

27. L Almasy and J Blangero: Endophenotypes as quantitative risk factors for psychiatric disease: rationale and study design. Am J Med Genet 105, 42-4 (2001)
DOI: 10.1002/1096-8628(20010108)105:1<42::AID-AJMG1055>3.0.CO;2-9

28. G Buzsaki and A Draguhn: Neuronal oscillations in cortical networks. Science 304, 1926-9 (2004)
DOI: 10.1126/science.1099745

29. R Cossart, D Aronov, and R Yuste: Attractor dynamics of network UP states in the neocortex. Nature 423, 283-8 (2003)
DOI: 10.1038/nature01614

30. JF Poulet and CC Petersen: Internal brain state regulates membrane potential synchrony in barrel cortex of behaving mice. Nature 454, 881-5 (2008)
DOI: 10.1038/nature07150

31. P Rigas, and Castro-Alamancos, M.A.: Thalamocortical Up states: differential effects of intrinsic and extrinsic cortical inputs on persistent activity. J Neurosci 27, 4261-4272 (2007)
DOI: 10.1523/JNEUROSCI.0003-07.2007

32. P Rigas, and Castro-Alamancos M.A. : Impact of persistent cortical activity (Up states) on intracortical and thalamocortical synaptic inputs. J Neurophysiol 102, 119-31 (2009)
DOI: 10.1152/jn.00126.2009

33. MV Sanchez-Vives and DA McCormick: Cellular and network mechanisms of rhythmic recurrent activity in neocortex. Nat Neurosci 3, 1027-34 (2000)
DOI: 10.1038/79848

34. M Steriade, A Nunez, and F Amzica: A novel slow (< 1 Hz) oscillation of neocortical neurons in vivo: depolarizing and hyperpolarizing components. J Neurosci 13, 3252-65 (1993)

35. M Steriade, I Timofeev, and F Grenier: Natural waking and sleep states: a view from inside neocortical neurons. J Neurophysiol 85, 1969-85 (2001)

36. JN MacLean, BO Watson, GB Aaron, and R Yuste: Internal dynamics determine the cortical response to thalamic stimulation. Neuron 48, 811-23 (2005)
DOI: 10.1016/j.neuron.2005.09.035

37. B Haider, A Duque, AR Hasenstaub, and DA McCormick: Neocortical network activity in vivo is generated through a dynamic balance of excitation and inhibition. J Neurosci 26, 4535-45 (2006)
DOI: 10.1523/JNEUROSCI.5297-05.2006

38. R Yuste, JN MacLean, J Smith, and A Lansner: The cortex as a central pattern generator. Nat Rev Neurosci 6, 477-83 (2005)
DOI: 10.1038/nrn1686

39. A Hasenstaub, Y Shu, B Haider, U Kraushaar, A Duque, and DA McCormick: Inhibitory postsynaptic potentials carry synchronized frequency information in active cortical networks. Neuron 47, 423-35 (2005)
DOI: 10.1016/j.neuron.2005.06.016

40. MV Sanchez-Vives, and McCormick, D.A Cellular and network mechanisms of rhythmic recurrent activity in neocortex. Nat Neurosci 3, 1027-1034 (2000)
DOI: 10.1038/79848

41. Y Shu, A Hasenstaub, and DA McCormick: Turning on and off recurrent balanced cortical activity. Nature 423, 288-93 (2003)
DOI: 10.1038/nature01616

42. T Bourgeron: A synaptic trek to autism. Curr Opin Neurobiol 19, 231-4 (2009)
DOI: 10.1016/j.conb.2009.06.003

43. J Ziburkus, JR Cressman, and SJ Schiff: Seizures as imbalanced up states: excitatory and inhibitory conductances during seizure-like events. J Neurophysiol 109, 1296-306 (2013)
DOI: 10.1152/jn.00232.2012

44. MA Castro-Alamancos: Dynamics of sensory thalamocortical synaptic networks during information processing states. Prog Neurobiol 74, 213-47 (2004)
DOI: 10.1016/j.pneurobio.2004.09.002

45. M Steriade, D Contreras, R Curro Dossi, and A Nunez: The slow (< 1 Hz) oscillation in reticular thalamic and thalamocortical neurons: scenario of sleep rhythm generation in interacting thalamic and neocortical networks. J Neurosci 13, 3284-99 (1993)

46. M Steriade, A Nunez, and F Amzica: Intracellular analysis of relations between the slow (< 1 Hz) neocortical oscillation and other sleep rhythms of the electroencephalogram. J Neurosci 13, 3266-83 (1993)

47. M Steriade, DA McCormick, and TJ Sejnowski: Thalamocortical oscillations in the sleeping and aroused brain. Science 262, 679-85 (1993)
DOI: 10.1126/science.8235588

48. I Lampl, I Reichova, and D Ferster: Synchronous membrane potential fluctuations in neurons of the cat visual cortex. Neuron 22, 361-74 (1999)
DOI: 10.1016/S0896-6273(00)81096-X

49. CC Petersen, TT Hahn, M Mehta, A Grinvald, and B Sakmann: Interaction of sensory responses with spontaneous depolarization in layer 2/3 barrel cortex. Proc Natl Acad Sci U S A 100, 13638-43 (2003)
DOI: 10.1073/pnas.2235811100

50. F Amzica and M Steriade: Short- and long-range neuronal synchronization of the slow (< 1 Hz) cortical oscillation. J Neurophysiol 73, 20-38 (1995)

51. MA Castro-Alamancos and E Oldford: Cortical sensory suppression during arousal is due to the activity-dependent depression of thalamocortical synapses. J Physiol (Lond) 541, 319-31 (2002)
DOI: 10.1113/jphysiol.2002.016857

52. G Moruzzi and HW Magoun: Brain stem reticular formation and activation of the EEG. Electroencephalogr Clin Neurophysiol 1, 455-73 (1949)
DOI: 10.1016/0013-4694(49)90219-9

53. G Buzsaki, RG Bickford, G Ponomareff, LJ Thal, R Mandel, and FH Gage: Nucleus basalis and thalamic control of neocortical activity in the freely moving rat. J Neurosci 8, 4007-26 (1988)

54. G Aston-Jones, C Chiang, and T Alexinsky: Discharge of noradrenergic locus coeruleus neurons in behaving rats and monkeys suggests a role in vigilance. Prog Brain Res 88, 501-20 (1991)
DOI: 10.1016/S0079-6123(08)63830-3

55. M Steriade, F Amzica, and A Nunez: Cholinergic and noradrenergic modulation of the slow (approximately 0.3. Hz) oscillation in neocortical cells. J Neurophysiol 70, 1385-400 (1993)

56. C Sigalas, P Rigas, P Tsakanikas, and I Skaliora: High-Affinity Nicotinic Receptors Modulate Spontaneous Cortical Up States In vitro. J Neurosci 35, 11196-208 (2015)
DOI: 10.1523/JNEUROSCI.5222-14.2015

57. M Favero, G Varghese, and MA Castro-Alamancos: The state of somatosensory cortex during neuromodulation. J Neurophysiol 108, 1010-24 (2012)
DOI: 10.1152/jn.00256.2012

58. D Contreras and M Steriade: Cellular basis of EEG slow rhythms: a study of dynamic corticothalamic relationships. J Neurosci 15, 604-22 (1995)

59. A Luczak, P Bartho, SL Marguet, G Buzsaki, and KD Harris: Sequential structure of neocortical spontaneous activity in vivo. Proc Natl Acad Sci U S A 104, 347-52 (2007)
DOI: 10.1073/pnas.0605643104

60. M Massimini, R Huber, F Ferrarelli, S Hill, and G Tononi: The sleep slow oscillation as a traveling wave. J Neurosci 24, 6862-70 (2004)
DOI: 10.1523/JNEUROSCI.1318-04.2004

61. F Amzica and M Steriade: Disconnection of intracortical synaptic linkages disrupts synchronization of a slow oscillation. J Neurosci 15, 4658-77 (1995)

62. RL Cowan and CJ Wilson: Spontaneous firing patterns and axonal projections of single corticostriatal neurons in the rat medial agranular cortex. J Neurophysiol 71, 17-32 (1994)

63. M Steriade, F Amzica, and D Contreras: Cortical and thalamic cellular correlates of electroencephalographic burst-suppression. Electroencephalogr Clin Neurophysiol 90, 1-16 (1994)
DOI: 10.1016/0013-4694(94)90108-2

64. DA McCormick: Cholinergic and noradrenergic modulation of thalamocortical processing. Trends Neurosci 12, 215-21 (1989)
DOI: 10.1016/0166-2236(89)90125-2

65. DA McCormick: Neurotransmitter actions in the thalamus and cerebral cortex and their role in neuromodulation of thalamocortical activity. Prog Neurobiol 39, 337-88 (1992)
DOI: 10.1016/0301-0082(92)90012-4

66. I Timofeev, F Grenier, M Bazhenov, TJ Sejnowski, and M Steriade: Origin of slow cortical oscillations in deafferented cortical slabs. Cereb Cortex 10, 1185-99 (2000)
DOI: 10.1093/cercor/10.12.1185

67. PA Schwartzkroin and DA Prince: Cellular and field potential properties of epileptogenic hippocampal slices. Brain Res 147, 117-30 (1978)
DOI: 10.1016/0006-8993(78)90776-X

68. MJ Gutnick, BW Connors, and DA Prince: Mechanisms of neocortical epileptogenesis in vitro. J Neurophysiol 48, 1321-35 (1982)

69. BW Connors: Initiation of synchronized neuronal bursting in neocortex. Nature 310, 685-7 (1984)
DOI: 10.1038/310685a0

70. T Bal and DA McCormick: What stops synchronized thalamocortical oscillations? Neuron 17, 297-308 (1996)
DOI: 10.1016/S0896-6273(00)80161-0

71. MA Castro-Alamancos, Rigas, P., Tawara-Hirata, Y.: Resonance (~10Hz) of excitatory networks in motor cortex: effects of voltage-dependent ion channel blockers. J Physiol (Lond) 578, 173–191 (2007)
DOI: 10.1113/jphysiol.2006.119016

72. MA Castro-Alamancos and P Rigas: Synchronized oscillations caused by disinhibition in rodent neocortex are generated by recurrent synaptic activity mediated by AMPA receptors. J Physiol (Lond) 542, 567-81 (2002)
DOI: 10.1113/jphysiol.2002.019059

73. P Rigas, and Castro-Alamancos, M.A. : Leading role of the piriform cortex over the neocortex in the generation of spontaneous interictal spikes during block of GABA(A) receptors. Neuroscience 124, 953-961 (2004)
DOI: 10.1016/j.neuroscience.2003.11.034

74. J Konopacki, MB MacIver, BH Bland, and SH Roth: Carbachol-induced EEG ‘theta’ activity in hippocampal brain slices. Brain Res 405, 196-8 (1987)
DOI: 10.1016/0006-8993(87)91009-2

75. MA Whittington, RD Traub, and JG Jefferys: Synchronized oscillations in interneuron networks driven by metabotropic glutamate receptor activation. Nature 373, 612-5 (1995)
DOI: 10.1038/373612a0

76. A Fisahn, FG Pike, EH Buhl, and O Paulsen: Cholinergic induction of network oscillations at 40 Hz in the hippocampus in vitro. Nature 394, 186-9 (1998)
DOI: 10.1038/28179

77. C Papatheodoropoulos and G Kostopoulos: Spontaneous, low frequency (approximately 2-3 Hz) field activity generated in rat ventral hippocampal slices perfused with normal medium. Brain Res Bull 57, 187-93 (2002)
DOI: 10.1016/S0361-9230(01)00738-9

78. C Wu, WP Luk, J Gillis, F Skinner, and L Zhang: Size does matter: generation of intrinsic network rhythms in thick mouse hippocampal slices. J Neurophysiol 93, 2302-17 (2005)
DOI: 10.1152/jn.00806.2004

79. EH Buhl, G Tamas, and A Fisahn: Cholinergic activation and tonic excitation induce persistent gamma oscillations in mouse somatosensory cortex in vitro. J Physiol (Lond) 513, 117-26 (1998)
DOI: 10.1111/j.1469-7793.1998.117by.x

80. V Tancredi, G Biagini, M D’Antuono, J Louvel, R Pumain, and M Avoli: Spindle-like thalamocortical synchronization in a rat brain slice preparation. J Neurophysiol 84, 1093-7 (2000)

81. M Steriade: Corticothalamic resonance, states of vigilance and mentation. Neuroscience 101, 243-76 (2000)
DOI: 10.1016/S0306-4522(00)00353-5

82. M Steriade: Grouping of brain rhythms in corticothalamic systems. Neuroscience 137, 1087-106 (2006)
DOI: 10.1016/j.neuroscience.2005.10.029

83. P Achermann and AA Borbely: Low-frequency (< 1 Hz) oscillations in the human sleep electroencephalogram. Neuroscience 81, 213-22 (1997)
DOI: 10.1016/S0306-4522(97)00186-3

84. M Massimini, F Ferrarelli, SK Esser, BA Riedner, R Huber, M Murphy, MJ Peterson, and G Tononi: Triggering sleep slow waves by transcranial magnetic stimulation. Proc Natl Acad Sci U S A 104, 8496-501 (2007)
DOI: 10.1073/pnas.0702495104

85. MA Castro-Alamancos: Origin of synchronized oscillations induced by neocortical disinhibition in vivo. J Neurosci. 20, 9195-206 (2000)

86. EK Lambe and GK Aghajanian: Hallucinogen-induced UP states in the brain slice of rat prefrontal cortex: role of glutamate spillover and NR2B-NMDA receptors. Neuropsychopharmacology 31, 1682-9 (2006)
DOI: 10.1038/sj.npp.1300944

87. H Blumenfeld and J Taylor: Why do seizures cause loss of consciousness? Neuroscientist 9, 301-10 (2003)
DOI: 10.1177/1073858403255624

88. A Destexhe and D Pare: Impact of network activity on the integrative properties of neocortical pyramidal neurons in vivo. J Neurophysiol 81, 1531-47 (1999)

89. A Destexhe, M Rudolph, and D Pare: The high-conductance state of neocortical neurons in vivo. Nat Rev Neurosci 4, 739-51 (2003)
DOI: 10.1038/nrn1198

90. M Rudolph, JG Pelletier, D Pare, and A Destexhe: Characterization of synaptic conductances and integrative properties during electrically induced EEG-activated states in neocortical neurons in vivo. J Neurophysiol 94, 2805-21 (2005)
DOI: 10.1152/jn.01313.2004

91. MA Castro-Alamancos: Cortical up and activated states: implications for sensory information processing. Neuroscientist 15, 625-34 (2009)
DOI: 10.1177/1073858409333074

92. TD Cannon and MC Keller: Endophenotypes in the genetic analyses of mental disorders. Annu Rev Clin Psychol 2, 267-90 (2006)
DOI: 10.1146/annurev.clinpsy.2.022305.095232

93. S Crochet and CC Petersen: Correlating whisker behavior with membrane potential in barrel cortex of awake mice. Nat Neurosci 9, 608-10 (2006)
DOI: 10.1038/nn1690

94. MJ Gandal, JC Edgar, RS Ehrlichman, M Mehta, TP Roberts, and SJ Siegel: Validating gamma oscillations and delayed auditory responses as translational biomarkers of autism. Biol Psychiatry 68, 1100-6 (2010)
DOI: 10.1016/j.biopsych.2010.09.031

95. J Kissler, MM Muller, T Fehr, B Rockstroh, and T Elbert: MEG gamma band activity in schizophrenia patients and healthy subjects in a mental arithmetic task and at rest. Clin Neurophysiol 111, 2079-87 (2000)
DOI: 10.1016/S1388-2457(00)00425-9

96. C Sorg, V Riedl, M Muhlau, VD Calhoun, T Eichele, L Laer, A Drzezga, H Forstl, A Kurz, C Zimmer, and AM Wohlschlager: Selective changes of resting-state networks in individuals at risk for Alzheimer’s disease. Proc Natl Acad Sci U S A 104, 18760-5 (2007)
DOI: 10.1073/pnas.0708803104

97. Y Wada, Y Nanbu, M Kikuchi, Y Koshino, and T Hashimoto: Aberrant functional organization in schizophrenia: analysis of EEG coherence during rest and photic stimulation in drug-naive patients. Neuropsychobiology 38, 63–9 (1998)
DOI: 10.1159/000026518

98. EN Arnautova and TN Nesmeianova: A Proposed International Classification of Epileptic Seizures. Epilepsia 5, 297-306 (1964)
DOI: 10.1111/j.1528-1157.1964.tb03337.x

99. JH Jackson: A study of convulsions. Trans St Andrews Med Grad Assn 3, 1-45 (1870)

100. H Matsumoto and CA Marsan: Cortical Cellular Phenomena in Experimental Epilepsy: Interictal Manifestations. Exp Neurol 9, 286-304 (1964)
DOI: 10.1016/0014-4886(64)90025-1

101. H Matsumoto and CA Marsan: Cortical Cellular Phenomena in Experimental Epilepsy: Ictal Manifestations. Exp Neurol 9, 305-26 (1964)
DOI: 10.1016/0014-4886(64)90026-3

102. TF Enomoto and C Ajmone-Marsan: Epileptic activation of single cortical neurons and their relationship with electroencephalographic discharges. Electroencephalogr Clin Neurophysiol 11, 199-218 (1959)
DOI: 10.1016/0013-4694(59)90076-8

103. DA Prince and D Farell: “Centrencephalic” spike-wave discharges following parenteral penicillin injection in the cat. Neurology 19, 309-310 (1969)

104. M Steriade and G Yossif: Spike-and-wave afterdischarges in cortical somatosensory neurons of cat. Electroencephalogr Clin Neurophysiol 37, 633-48 (1974)
DOI: 10.1016/0013-4694(74)90076-5

105. I Timofeev, F Grenier, and M Steriade: Contribution of intrinsic neuronal factors in the generation of cortically driven electrographic seizures. J Neurophysiol 92, 1133-43 (2004)
DOI: 10.1152/jn.00523.2003

106. G Kostopoulos, M Avoli, A Pellegrini, and P Gloor: Laminar analysis of spindles and of spikes of the spike and wave discharge of feline generalized penicillin epilepsy. Electroencephalogr Clin Neurophysiol 53, 1-13 (1982)
DOI: 10.1016/0013-4694(82)90101-8

107. MA Castro-Alamancos: Vibrissa myoclonus (rhythmic retractions) driven by resonance of excitatory networks in motor cortex. J Neurophysiol 96, 1691-8 (2006)
DOI: 10.1152/jn.00454.2006

108. K Krnjevic: GABAergic inhibition in the neocortex. J Mind Behav 8, 537-547 (1987)

109. BW Connors, Malenka, R.C. and Silva, L.R.: Two-inhibitory postsynaptic potentials, and GABAA and GABAB receptor-mediated responses in neocortex of rat and cat. J Physiol (Lond) 406, 443-468 (1988)
DOI: 10.1113/jphysiol.1988.sp017390

110. MA Castro-Alamancos: The motor cortex: a network tuned to 7-14 Hz. Front Neural Circuits 7, 21 (2013)
DOI: 10.3389/fncir.2013.00021

111. HK Manji, JA Quiroz, J Sporn, JL Payne, K Denicoff, AG N, CA Zarate, Jr., and DS Charney: Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult-to-treat depression. Biol Psychiatry 53, 707-42 (2003)
DOI: 10.1016/S0006-3223(03)00117-3

112. GS Berns and CB Nemeroff: The neurobiology of bipolar disorder. Am J Med Genet C Semin Med Genet 123C, 76-84 (2003)
DOI: 10.1002/ajmg.c.20016

113. JH Krystal, DF Tolin, G Sanacora, SA Castner, GV Williams, DE Aikins, RE Hoffman, and DC D’Souza: Neuroplasticity as a target for the pharmacotherapy of anxiety disorders, mood disorders, and schizophrenia. Drug Discov Today 14, 690-7 (2009)
DOI: 10.1016/j.drudis.2009.05.002

114. PM Matthews, GD Honey, and ET Bullmore: Applications of fMRI in translational medicine and clinical practice. Nat Rev Neurosci 7, 732-44 (2006)
DOI: 10.1038/nrn1929

115. P Rigas, DA Adamos, C Sigalas, P Tsakanikas, NA Laskaris, and I Skaliora: Spontaneous Up states in vitro: a single-metric index of the functional maturation and regional differentiation of the cerebral cortex. Front Neural Circuits 9, 59 (2015)
DOI: 10.3389/fncir.2015.00059

116. P Rigas, LJ Leontiadis, P Tsakanikas, and I Skaliora: Spontaneous Neuronal Network Persistent Activity in the Neocortex: A(n) (Endo)phenotype of Brain (Patho)physiology. Adv Exp Med Biol 988, 235-247 (2017)
DOI: 10.1007/978-3-319-56246-9_19

117. Fmr1 knockout mice: a model to study fragile X mental retardation. The Dutch-Belgian Fragile X Consortium. Cell 78, 23-33 (1994)

118. RJ Hagerman, MY Ono, and PJ Hagerman: Recent advances in fragile X: a model for autism and neurodegeneration. Curr Opin Psychiatry 18, 490-6 (2005)
DOI: 10.1097/01.yco.0000179485.39520.b0

119. WE Kaufmann, R Cortell, AS Kau, I Bukelis, E Tierney, RM Gray, C Cox, GT Capone, and P Stanard: Autism spectrum disorder in fragile X syndrome: communication, social interaction, and specific behaviors. Am J Med Genet A 129A, 225-34 (2004)
DOI: 10.1002/ajmg.a.30229

120. AJ Verkerk, M Pieretti, JS Sutcliffe, YH Fu, DP Kuhl, A Pizzuti, O Reiner, S Richards, MF Victoria, FP Zhang, and et al.: Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65, 905-14 (1991)
DOI: 10.1016/0092-8674(91)90397-H

121. P Jin and ST Warren: Understanding the molecular basis of fragile X syndrome. Hum Mol Genet 9, 901-8 (2000)
DOI: 10.1093/hmg/9.6.901

122. BE Pfeiffer and KM Huber: Fragile X mental retardation protein induces synapse loss through acute postsynaptic translational regulation. J Neurosci 27, 3120-30 (2007)
DOI: 10.1523/JNEUROSCI.0054-07.2007

123. SA Irwin, B Patel, M Idupulapati, JB Harris, RA Crisostomo, BP Larsen, F Kooy, PJ Willems, P Cras, PB Kozlowski, RA Swain, IJ Weiler, and WT Greenough: Abnormal dendritic spine characteristics in the temporal and visual cortices of patients with fragile-X syndrome: a quantitative examination. Am J Med Genet 98, 161-7 (2001)
DOI: 10.1002/1096-8628(20010115)98:2<161::AID-AJMG1025>3.0.CO;2-B

124. I Bureau, GM Shepherd, and K Svoboda: Circuit and plasticity defects in the developing somatosensory cortex of FMR1 knock-out mice. J Neurosci 28, 5178-88 (2008)
DOI: 10.1523/JNEUROSCI.1076-08.2008

125. A Hazra, F Gu, A Aulakh, C Berridge, JL Eriksen, and J Ziburkus: Inhibitory neuron and hippocampal circuit dysfunction in an aged mouse model of Alzheimer’s disease. PLoS One 8, e64318 (2013)
DOI: 10.1371/journal.pone.0064318

126. DD Krueger, EK Osterweil, SP Chen, LD Tye, and MF Bear: Cognitive dysfunction and prefrontal synaptic abnormalities in a mouse model of fragile X syndrome. Proc Natl Acad Sci U S A 108, 2587-92 (2011)
DOI: 10.1073/pnas.1013855108

127. GJ Bassell and ST Warren: Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function. Neuron 60, 201-14 (2008)
DOI: 10.1016/j.neuron.2008.10.004

128. KM Huber, SM Gallagher, ST Warren, and MF Bear: Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc Natl Acad Sci U S A 99, 7746-50 (2002)
DOI: 10.1073/pnas.122205699

129. A Cruz-Martin, M Crespo, and C Portera-Cailliau: Delayed stabilization of dendritic spines in fragile X mice. J Neurosci 30, 7793-803 (2010)
DOI: 10.1523/JNEUROSCI.0577-10.2010

130. PM Rodier, JL Ingram, B Tisdale, S Nelson, and J Romano: Embryological origin for autism: developmental anomalies of the cranial nerve motor nuclei. J Comp Neurol 370, 247-61 (1996)
DOI: 10.1002/(SICI)1096-9861(19960624)370:2<247::AID-CNE8>3.0.CO;2-2

131. T Rinaldi, K Kulangara, K Antoniello, and H Markram: Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid. Proc Natl Acad Sci U S A 104, 13501-6 (2007)
DOI: 10.1073/pnas.0704391104

132. T Rinaldi, G Silberberg, and H Markram: Hyperconnectivity of local neocortical microcircuitry induced by prenatal exposure to valproic acid. Cereb Cortex 18, 763-70 (2008)
DOI: 10.1093/cercor/bhm117

133. G Dendrinos, M Hemelt, and A Keller: Prenatal VPA Exposure and Changes in Sensory Processing by the Superior Colliculus. Front Integr Neurosci 5, 68 (2011)
DOI: 10.3389/fnint.2011.00068

134. MA Edalatmanesh, H Nikfarjam, F Vafaee, and M Moghadas: Increased hippocampal cell density and enhanced spatial memory in the valproic acid rat model of autism. Brain Res 1526, 15-25 (2013)
DOI: 10.1016/j.brainres.2013.06.024

135. N Sosa-Diaz, ME Bringas, M Atzori, and G Flores: Prefrontal cortex, hippocampus, and basolateral amygdala plasticity in a rat model of autism spectrum. Synapse 68, 468-73 (2014)
DOI: 10.1002/syn.21759

136. D Cheaha, S Bumrungsri, S Chatpun, and E Kumarnsit: Characterization of in utero valproic acid mouse model of autism by local field potential in the hippocampus and the olfactory bulb. Neurosci Res 98, 28-34 (2015)
DOI: 10.1016/j.neures.2015.04.006

137. D Cheaha and E Kumarnsit: Alteration of spontaneous spectral powers and coherences of local field potential in prenatal valproic acid mouse model of autism. Acta Neurobiol Exp (Wars) 75, 351-63 (2015)

138. SM Hamilton, JR Green, S Veeraragavan, L Yuva, A McCoy, Y Wu, J Warren, L Little, D Ji, X Cui, E Weinstein, and R Paylor: Fmr1 and Nlgn3 knockout rats: novel tools for investigating autism spectrum disorders. Behav Neurosci 128, 103-9 (2014)
DOI: 10.1037/a0035988

139. RA Gibbs, GM Weinstock, ML Metzker, DM Muzny, EJ Sodergren, S Scherer, G Scott, D Steffen, KC Worley, PE Burch, G Okwuonu, S Hines, L Lewis, C DeRamo, O Delgado, S Dugan-Rocha, G Miner, M Morgan, A Hawes, R Gill, Celera, RA Holt, MD Adams, PG Amanatides, H Baden-Tillson, M Barnstead, S Chin, CA Evans, S Ferriera, C Fosler, A Glodek, Z Gu, D Jennings, CL Kraft, T Nguyen, CM Pfannkoch, C Sitter, GG Sutton, JC Venter, T Woodage, D Smith, HM Lee, E Gustafson, P Cahill, A Kana, L Doucette-Stamm, K Weinstock, K Fechtel, RB Weiss, DM Dunn, ED Green, RW Blakesley, GG Bouffard, PJ De Jong, K Osoegawa, B Zhu, M Marra, J Schein, I Bosdet, C Fjell, S Jones, M Krzywinski, C Mathewson, A Siddiqui, N Wye, J McPherson, S Zhao, CM Fraser, J Shetty, S Shatsman, K Geer, Y Chen, S Abramzon, WC Nierman, PH Havlak, R Chen, KJ Durbin, A Egan, Y Ren, XZ Song, B Li, Y Liu, X Qin, S Cawley, AJ Cooney, LM D’Souza, K Martin, JQ Wu, ML Gonzalez-Garay, AR Jackson, KJ Kalafus, MP McLeod, A Milosavljevic, D Virk, A Volkov, DA Wheeler, Z Zhang, JA Bailey, EE Eichler, E Tuzun, E Birney, E Mongin, A Ureta-Vidal, C Woodwark, E Zdobnov, P Bork, M Suyama, D Torrents, M Alexandersson, BJ Trask, JM Young, H Huang, H Wang, H Xing, S Daniels, D Gietzen, J Schmidt, K Stevens, U Vitt, J Wingrove, F Camara, M Mar Alba, JF Abril, R Guigo, A Smit, I Dubchak, EM Rubin, O Couronne, A Poliakov, N Hubner, D Ganten, C Goesele, O Hummel, T Kreitler, YA Lee, J Monti, H Schulz, H Zimdahl, H Himmelbauer, H Lehrach, HJ Jacob, S Bromberg, J Gullings-Handley, MI Jensen-Seaman, AE Kwitek, J Lazar, D Pasko, PJ Tonellato, S Twigger, CP Ponting, JM Duarte, S Rice, L Goodstadt, SA Beatson, RD Emes, EE Winter, C Webber, P Brandt, G Nyakatura, M Adetobi, F Chiaromonte, L Elnitski, P Eswara, RC Hardison, M Hou, D Kolbe, K Makova, W Miller, A Nekrutenko, C Riemer, S Schwartz, J Taylor, S Yang, Y Zhang, K Lindpaintner, TD Andrews, M Caccamo, M Clamp, L Clarke, V Curwen, R Durbin, E Eyras, SM Searle, GM Cooper, S Batzoglou, M Brudno, A Sidow, EA Stone, BA Payseur, G Bourque, C Lopez-Otin, XS Puente, K Chakrabarti, S Chatterji, C Dewey, L Pachter, N Bray, VB Yap, A Caspi, G Tesler, PA Pevzner, D Haussler, KM Roskin, R Baertsch, H Clawson, TS Furey, AS Hinrichs, D Karolchik, WJ Kent, KR Rosenbloom, H Trumbower, M Weirauch, DN Cooper, PD Stenson, B Ma, M Brent, M Arumugam, D Shteynberg, RR Copley, MS Taylor, H Riethman, U Mudunuri, J Peterson, M Guyer, A Felsenfeld, S Old, S Mockrin and F Collins: Genome sequence of the Brown Norway rat yields insights into mammalian evolution. Nature 428, 493-521 (2004)
DOI: 10.1038/nature02426

140. RJ Hagerman and PJ Hagerman: The fragile X premutation: into the phenotypic fold. Curr Opin Genet Dev 12, 278-83 (2002)
DOI: 10.1016/S0959-437X(02)00299-X

141. RS Erzurumlu and P Gaspar: Development and critical period plasticity of the barrel cortex. Eur J Neurosci 35, 1540-53 (2012)
DOI: 10.1111/j.1460-9568.2012.08075.x

142. RS Erzurumlu and PC Kind: Neural activity: sculptor of ‘barrels’ in the neocortex. Trends Neurosci 24, 589-95 (2001)
DOI: 10.1016/S0166-2236(00)01958-5

143. G Lopez-Bendito and Z Molnar: Thalamocortical development: how are we going to get there? Nat Rev Neurosci 4, 276-89 (2003)
DOI: 10.1038/nrn1075

144. JR Gibson, AF Bartley, SA Hays, and KM Huber: Imbalance of neocortical excitation and inhibition and altered UP states reflect network hyperexcitability in the mouse model of fragile X syndrome. J Neurophysiol 100, 2615-26 (2008)
DOI: 10.1152/jn.90752.2008

145. SA Hays, KM Huber, and JR Gibson: Altered neocortical rhythmic activity states in Fmr1 KO mice are due to enhanced mGluR5 signaling and involve changes in excitatory circuitry. J Neurosci 31, 14223-34 (2011)
DOI: 10.1523/JNEUROSCI.3157-11.2011

146. A Contractor, VA Klyachko, and C Portera-Cailliau: Altered Neuronal and Circuit Excitability in Fragile X Syndrome. Neuron 87, 699-715 (2015)
DOI: 10.1016/j.neuron.2015.06.017

147. JT Goncalves, JE Anstey, P Golshani, and C Portera-Cailliau: Circuit level defects in the developing neocortex of Fragile X mice. Nat Neurosci 16, 903-9 (2013)
DOI: 10.1038/nn.3415

148. PW Anderson: More is Different. Science 177 (1972)
DOI: 10.1126/science.177.4047.393

149. AP Alivisatos, M Chun, GM Church, RJ Greenspan, ML Roukes, and R Yuste: The brain activity map project and the challenge of functional connectomics. Neuron 74, 970-4 (2012)
DOI: 10.1016/j.neuron.2012.06.006

150. PR Huttenlocher: Synaptic density in human frontal cortex - developmental changes and effects of aging. Brain Res 163, 195-205 (1979)
DOI: 10.1016/0006-8993(79)90349-4

151. JY Sebe, EC Looke-Stewart, RC Estrada, and SC Baraban: Robust tonic GABA currents can inhibit cell firing in mouse newborn neocortical pyramidal cells. Eur J Neurosci 32, 1310-8 (2010)
DOI: 10.1111/j.1460-9568.2010.07373.x

152. Y Ben-Ari: The GABA excitatory/inhibitory developmental sequence: a personal journey. Neuroscience 279, 187-219 (2014)
DOI: 10.1016/j.neuroscience.2014.08.001

153. M Landers and H Philip Zeigler: Development of rodent whisking: trigeminal input and central pattern generation. Somatosens Mot Res 23, 1-10 (2006)
DOI: 10.1080/08990220600700768

154. P Sengupta: The Laboratory Rat: Relating Its Age With Human’s. Int J Prev Med 4, 624-30 (2013)

155. Y Clermont and B Perey: Quantitative study of the cell population of the seminiferous tubules in immature rats. Am J Anat 100, 241-67 (1957)
DOI: 10.1002/aja.1001000205

156. KD Dohler and W Wuttke: Changes with age in levels of serum gonadotropins, prolactin and gonadal steroids in prepubertal male and female rats. Endocrinology 97, 898-907 (1975)
DOI: 10.1210/endo-97-4-898

157. LP Spear and SC Brake: Periadolescence: age-dependent behavior and psychopharmacological responsivity in rats. Dev Psychobiol 16, 83-109 (1983)
DOI: 10.1002/dev.420160203

158. A Pickles, K Pickering, E Simonoff, J Silberg, J Meyer, and H Maes: Genetic “clocks” and “soft” events: a twin model for pubertal development and other recalled sequences of developmental milestones, transitions, or ages at onset. Behav Genet 28, 243-53 (1998)
DOI: 10.1023/A:1021615228995

159. L Spear: Modeling adolescent development and alcohol use in animals. Alcohol Res Health 24, 115-23 (2000)

160. J Dobbing and J Sands: Comparative aspects of the brain growth spurt. Early Hum Dev 3, 79-83 (1979)
DOI: 10.1016/0378-3782(79)90022-7

161. A Gottlieb, I Keydar, and HT Epstein: Rodent brain growth stages: an analytical review. Biol Neonate 32, 166-76 (1977)
DOI: 10.1159/000241012

162. SL Moshe: Epileptogenesis and the immature brain. Epilepsia 28 Suppl 1, S3-15 (1987)
DOI: 10.1111/j.1528-1157.1987.tb05753.x

163. A Nehlig: Cerebral energy metabolism, glucose transport and blood flow: changes with maturation and adaptation to hypoglycaemia. Diabetes Metab 23, 18-29 (1997)

164. S Avishai-Eliner, KL Brunson, CA Sandman, and TZ Baram: Stressed-out, or in (utero)? Trends Neurosci 25, 518-24 (2002)
DOI: 10.1016/S0166-2236(02)02241-5

165. L Velisek and SL Moshe: Effects of brief seizures during development. Prog Brain Res 135, 355-64 (2002)
DOI: 10.1016/S0079-6123(02)35032-5

166. SR Ojeda, WW Andrews, JP Advis, and SS White: Recent advances in the endocrinology of puberty. Endocr Rev 1, 228-57 (1980)
DOI: 10.1210/edrv-1-3-228

167. H Li and MC Crair: How do barrels form in somatosensory cortex? Ann N Y Acad Sci 1225, 119-29 (2011)
DOI: 10.1111/j.1749-6632.2011.06024.x

168. JP Donoghue and SP Wise: The motor cortex of the rat: cytoarchitecture and microstimulation mapping. J Comp Neurol 212, 76-88 (1982)
DOI: 10.1002/cne.902120106

169. MA Castro-Alamancos and BW Connors: Short-term synaptic enhancement and long-term potentiation in neocortex. Proc Natl Acad Sci U S A 93, 1335-9 (1996)
DOI: 10.1073/pnas.93.3.1335

170. MA Castro-Alamancos, JP Donoghue, and BW Connors: Different forms of synaptic plasticity in somatosensory and motor areas of the neocortex. J Neurosci 15, 5324-33 (1995)

171. MA Castro-Alamancos and BW Connors: Spatiotemporal properties of short-term plasticity sensorimotor thalamocortical pathways of the rat. J Neurosci 16, 2767-79 (1996)

172. MA Castro-Alamancos and Y Tawara-Hirata: Area-specific resonance of excitatory networks in neocortex: control by outward currents. Epilepsia 48, 1572-84 (2007)
DOI: 10.1111/j.1528-1167.2007.01113.x

173. GK Aghajanian: Modeling “psychosis” in vitro by inducing disordered neuronal network activity in cortical brain slices. Psychopharmacology (Berl), 206, 575-85 (2009)
DOI: 10.1007/s00213-009-1484-9

174. M Iacoboni and M Dapretto: The mirror neuron system and the consequences of its dysfunction. Nat Rev Neurosci 7, 942-51 (2006)
DOI: 10.1038/nrn2024

175. M Dapretto, MS Davies, JH Pfeifer, AA Scott, M Sigman, SY Bookheimer, and M Iacoboni: Understanding emotions in others: mirror neuron dysfunction in children with autism spectrum disorders. Nat Neurosci 9, 28-30 (2006)
DOI: 10.1038/nn1611

176. CD Frith and U Frith: The neural basis of mentalizing. Neuron 50, 531-4 (2006)
DOI: 10.1016/j.neuron.2006.05.001

Key Words: cerebral cortex, Up states, persistent activity, spontaneous, slow oscillations, development, autism, endophenotype, Review

Send correspondence to: Pavlos Rigas, Neurophysiology Lab, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece, Tel: 30 210 6597439, Fax: 30 210 6597545, E-mail: pavlosrigas@gmail.com