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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
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