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Table 1 Animal ASD models with reported alterations in PV immunoreactivity, mitochondria dysfunction or hyper/hypo-connectivity

From: Absence of parvalbumin increases mitochondria volume and branching of dendrites in inhibitory Pvalb neurons in vivo: a point of convergence of autism spectrum disorder (ASD) risk gene phenotypes

Protein / Gene Mouse (animal) model or Treatment

Altered PV staining/ PV+ number

Mitochondria dysfunction

Hyper/hypo-connectivty

SFARIa

Shank 3 (Shank3) Shank3B-/-

PV+ puncta surrounding pyramidal cells decreased in insular cortex of adult mice [1]c, PV downregulation in striatal Pvalb neurons at PND25 [2]

In a Fmr1 knock-in premutation mouse model resulting in Shank3 downregulation, at PND21, decreases in NADH oxidase, succinate oxidase and cytochrome c oxidase activity, as well as increased uncoupling between ATP production and electron transfer in hippocampus and cerebellum [3]

Altered local and global connectivity patterns indicative of circuit abnormalities in SHANK3-mutant macaques [4], prefrontal hypoconnectivity associated with reduced density of short-range cortical projections [5], reduced spine density in striatum of Shank3(Δex4–22)-/- mice linked to abnormal functional connectivity within the cortico-striatal-thalamic circuit [6]

1 (Sb)

phosphatase and tensin homolog (Pten) Pten+/-

n/a

Increase of several mitochondrial complex activities (II-III, IV and V) in mitochondria isolated from hippocampus and cerebellum (not cortex) of young (4-6 weeks) mice, not accompanied by increases in mitochondrial mass [7]

Increased axonal branching and connectivity (mPFC to basolateral amygdala axonal projections) [8], local and long-range hyper-connectivity in auditory cortex [9]

1 (S)

methyl CpG binding protein 2 (Mecp2) Mecp2-/-

At PND15 no PV+ cells [10] indicates delayed maturation of Pvalb neurons, but morphological hypermaturation in visual cortex is associated with increased Pvalb mRNA [11]

Increased ROS release in mitochondria isolated from hippocampus of Mecp2-/- mice [12], increased H2O2 generation in mitochondria isolated from whole brain mainly produced by dysfunctional complex II [13]

Increase of Pvalb neuron cellular and PNN structural complexity in visual cortex [14], reduced density of excitatory dendritic spines in mPFC pyramidal cells [11]

2 (S)

contactin associated protein-like 2 (Cntnap2) Cntnap2-/-

Reduction in PV+ neurons in striatum and cortex at PND14 [15], PV downregulation in striatal Pvalb neurons at PND25 [16]

n/a

Decreased excitatory and inhibitory inputs onto mPFC L2/3 pyramidal neurons, concurrent with reduced spines and synapses [17], reduced long-range and local functional connectivity in prefrontal and midline brain "connectivity hubs" [18], major connectivity deficits in prefrontal and limbic pathways developing between adolescence and adulthood [19]

2 (S)

neuroligin 3 (Nlgn3) Nlgn3R451C

Asymmetric “patchy” PV-deficit in cortex at PND >60 [20]

n/a

Reduction in neuron firing synchrony in dissociated cultures of rat hippocampal neurons caused by a decrease in the complexity of axonal architecture [21]

2

fragile X mental retardation protein (Fmr1) Fmr1-/-

PV+ neurons reduced in somatosensory cortex layers II-VI in mice > 1 year [22]

Increased mitochondrial ROS production, impaired complex I activity, and increased mtDNA deletions in fibroblasts from Fmr1 KI mice (described in [3]) [23], mitochondria isolated from dfmr1-/- Drosophila thoraces show increased maximum electron transport system capacity under supersaturating conditions [24]

Anatomical hyperconnectivity in the primary visual cortex (V1), but a disproportional low connectivity of V1 with other neocortical regions [25], hyperconnectivity between neighbouring layer 5 pyramidal neurons during a critical period in early mPFC development [26], but robust hypoconnectivity phenotype in cortico-cortical and cortico-striatal circuits in PND30 mice [19]

3 (S)

Parvalbumin (Pvalb) PV+/- and PV-/-

≈30% reduction of PV+ cells in PV+/- mice in mPFC, SSC and striatum, no changes in numbers of Pvalb neurons in PV+/- and PV-/- mice at PND25 [2]

Increase in mitochondria volume and density in soma of Pvalb neurons and increased density and length of dendritic mitochondria in absence of PV expression [this study]

Increase in dendrite length (DG) and branching (striatum), as well as thickness of proximal dendrites (molecular layer interneurons) of selected PV-/- Pvalb neurons (age 3 – 5 months) [this study]

5

Valproic acid (VPA) Treatment

Asymmetric PV deficit in cortex/hippocampus at PND >60 [20], PV downregulation in striatal Pvalb neurons at PND25 [27]

The antioxidant resveratrol shown to improve the mitochondria function of cells reverses decreases in gephryn expression observed in VPA-treated rats and restores the proportion of PV+ cells in the amygdala [28]

Increased synaptophysin immunostaining in mPFC and a synaptophysin deficit in all hippocampal subfields [29], enhancement of the local recurrent functional connectivity formed by neocortical pyramidal neurons, but diminished number of putative synaptic contacts in connections between layer 5 pyramidal neurons [30]

n/a

  1. aSimons Foundation Autism Research Initiative (SFARI) gene scoring system (https://www.sfari.org/resource/sfari-gene/)
  2. bS human syndromic
  3. cReferences for data summarized in Table 1
  4. [1] Gogolla, N., Takesian, A.E., Feng, G., Fagiolini, M. and Hensch, T.K. (2014). Sensory integration in mouse insular cortex reflects GABA circuit maturation. Neuron 83, 894-905.
  5. [2] Filice, F., Vorckel, K.J., Sungur, A.O., Wöhr, M. and Schwaller, B. (2016). Reduction in parvalbumin expression not loss of the parvalbumin-expressing GABA interneuron subpopulation in genetic parvalbumin and shank mouse models of autism. Mol Brain 9, 10.
  6. [3] Napoli, E. et al. (2016). Premutation in the Fragile X Mental Retardation 1 (FMR1) Gene Affects Maternal Zn-milk and Perinatal Brain Bioenergetics and Scaffolding. Front Neurosci 10, 159.
  7. [4] Zhou, Y. et al. (2019). Atypical behaviour and connectivity in SHANK3-mutant macaques. Nature 570, 326-331.
  8. [5] Pagani, M. et al. (2019). Deletion of Autism Risk Gene Shank3 Disrupts Prefrontal Connectivity. J Neurosci 39, 5299-5310.
  9. [6] Wang, X. et al. (2016). Altered mGluR5-Homer scaffolds and corticostriatal connectivity in a Shank3 complete knockout model of autism. Nat Commun 7, 11459.
  10. [7] Napoli, E. et al. (2012). Mitochondrial dysfunction in Pten haplo-insufficient mice with social deficits and repetitive behavior: interplay between Pten and p53. PLoS One 7, e42504.
  11. [8] Huang, W.C., Chen, Y. and Page, D.T. (2016). Hyperconnectivity of prefrontal cortex to amygdala projections in a mouse model of macrocephaly/autism syndrome. Nat Commun 7, 13421.
  12. [9] Xiong, Q., Oviedo, H.V., Trotman, L.C. and Zador, A.M. (2012). PTEN regulation of local and long-range connections in mouse auditory cortex. J Neurosci 32, 1643-52.
  13. [10] Fukuda, T., Itoh, M., Ichikawa, T., Washiyama, K. and Goto, Y. (2005). Delayed maturation of neuronal architecture and synaptogenesis in cerebral cortex of Mecp2-deficient mice. J Neuropathol Exp Neurol 64, 537-44.
  14. [11] Patrizi, A., Awad, P.N., Chattopadhyaya, B., Li, C., Di Cristo, G. and Fagiolini, M. (2019). Accelerated Hyper-Maturation of Parvalbumin Circuits in the Absence of MeCP2. Cereb Cortex doi: 10.1093/cercor/bhz085
  15. [12] Can, K., Menzfeld, C., Rinne, L., Rehling, P., Kugler, S., Golubiani, G., Dudek, J. and Muller, M. (2019). Neuronal Redox-Imbalance in Rett Syndrome Affects Mitochondria as Well as Cytosol, and Is Accompanied by Intensified Mitochondrial O2 Consumption and ROS Release. Front Physiol 10, 479.
  16. [13] De Filippis, B. et al. (2015). Mitochondrial free radical overproduction due to respiratory chain impairment in the brain of a mouse model of Rett syndrome: protective effect of CNF1. Free Radic Biol Med 83, 167-77.
  17. [14] Sceniak, M.P., Lang, M., Enomoto, A.C., James Howell, C., Hermes, D.J. and Katz, D.M. (2016). Mechanisms of Functional Hypoconnectivity in the Medial Prefrontal Cortex of Mecp2 Null Mice. Cereb Cortex 26, 1938-1956.
  18. [15] Penagarikano, O. et al. (2011). Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits. Cell 147, 235-46.
  19. [16] Lauber, E., Filice, F. and Schwaller, B. (2018). Dysregulation of Parvalbumin Expression in the Cntnap2-/- Mouse Model of Autism Spectrum Disorder. Front Mol Neurosci 11, 262.
  20. [17] Lazaro, M.T. et al. (2019). Reduced Prefrontal Synaptic Connectivity and Disturbed Oscillatory Population Dynamics in the CNTNAP2 Model of Autism. Cell Rep 27, 2567-2578 e6.
  21. [18] Liska, A. et al. (2018). Homozygous Loss of Autism-Risk Gene CNTNAP2 Results in Reduced Local and Long-Range Prefrontal Functional Connectivity. Cereb Cortex 28, 1141-1153.
  22. [19] Zerbi, V. et al. (2018). Dysfunctional Autism Risk Genes Cause Circuit-Specific Connectivity Deficits With Distinct Developmental Trajectories. Cereb Cortex 28, 2495-2506.
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  24. [21] Gutierrez, R.C., Hung, J., Zhang, Y., Kertesz, A.C., Espina, F.J. and Colicos, M.A. (2009). Altered synchrony and connectivity in neuronal networks expressing an autism-related mutation of neuroligin 3. Neuroscience 162, 208-21.
  25. [22] Selby, L., Zhang, C. and Sun, Q.Q. (2007). Major defects in neocortical GABAergic inhibitory circuits in mice lacking the fragile X mental retardation protein. Neurosci Lett 412, 227-32.
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  30. [27] Lauber, E., Filice, F. and Schwaller, B. (2016). Prenatal Valproate Exposure Differentially Affects Parvalbumin-Expressing Neurons and Related Circuits in the Cortex and Striatum of Mice. Front Mol Neurosci 9, 150.
  31. [28] Fontes-Dutra, M. et al. (2018). Resveratrol Prevents Cellular and Behavioral Sensory Alterations in the Animal Model of Autism Induced by Valproic Acid. Front Synaptic Neurosci 10, 9.
  32. [29] Codagnone, M.G., Podesta, M.F., Uccelli, N.A. and Reines, A. (2015). Differential Local Connectivity and Neuroinflammation Profiles in the Medial Prefrontal Cortex and Hippocampus in the Valproic Acid Rat Model of Autism. Dev Neurosci 37, 215-31.
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Molecular Autism

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