1. Allison C, Matthews FE, Ruta L, Pasco G, Soufer R, Brayne C, Charman T, Baron-Cohen S. Quantitative Checklist for Autism in Toddlers (Q-CHAT). A population screening study with follow-up: the case for multiple time-point screening for autism. BMJ paediatrics open. 2021; 5(1): e000700.

OBJECTIVE: This is a prospective population screening study for autism in toddlers aged 18-30 months old using the Quantitative Checklist for Autism in Toddlers (Q-CHAT), with follow-up at age 4. DESIGN: Observational study. SETTING: Luton, Bedfordshire and Cambridgeshire in the UK. PARTICIPANTS: 13 070 toddlers registered on the Child Health Surveillance Database between March 2008 and April 2009, with follow-up at age 4; 3770 (29%) were screened for autism at 18-30 months using the Q-CHAT and the Childhood Autism Spectrum Test (CAST) at follow-up at age 4. INTERVENTIONS: A stratified sample across the Q-CHAT score distribution was invited for diagnostic assessment (phase 1). The 4-year follow-up included the CAST and the Checklist for Referral (CFR). All with CAST ≥15, phase 1 diagnostic assessment or with developmental concerns on the CFR were invited for diagnostic assessment (phase 2). Standardised diagnostic assessment at both time-points was conducted to establish the test accuracy of the Q-CHAT. MAIN OUTCOME MEASURES: Consensus diagnostic outcome at phase 1 and phase 2. RESULTS: At phase 1, 3770 Q-CHATs were returned (29% response) and 121 undertook diagnostic assessment, of whom 11 met the criteria for autism. All 11 screened positive on the Q-CHAT. The positive predictive value (PPV) at a cut-point of 39 was 17% (95% CI 8% to 31%). At phase 2, 2005 of 3472 CASTs and CFRs were returned (58% response). 159 underwent diagnostic assessment, including 82 assessed in phase 1. All children meeting the criteria for autism identified via the Q-CHAT at phase 1 also met the criteria at phase 2. The PPV was 28% (95% CI 15% to 46%) after phase 1 and phase 2. CONCLUSIONS: The Q-CHAT can be used at 18-30 months to identify autism and enable accelerated referral for diagnostic assessment. The low PPV suggests that for every true positive there would, however, be ~4-5 false positives. At follow-up, new cases were identified, illustrating the need for continued surveillance and rescreening at multiple time-points using developmentally sensitive instruments. Not all children who later receive a diagnosis of autism are detectable during the toddler period.

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2. Bellamy R, Ring H, Watson P, Kemp A, Munn G, Clare IC. The effect of ambient sounds on decision-making and heart rate variability in autism. Autism : the international journal of research and practice. 2021; 25(8): 2209-22.

Many autistic people report difficulties making decisions during everyday tasks, such as shopping. To examine the effect of sounds on decision-making, we developed a supermarket task where people watched a film shown from the shopper’s perspective and were asked to make decisions between different products. The task was divided into three sections and participants completed each section in a different auditory environment: (1) no sounds, (2) non-social sounds (e.g. fridges humming) and (3) social sounds (e.g. people talking). Thirty-eight autistic and 37 neurotypical adults took part. We measured decision-making by examining how long it took to make a decision and how consistent people were with their decisions. We also measured heart rate variability because this biological response provides a measure of anxiety. After the supermarket shopping task, participants told us in their own words about their experiences. Autistic participants said that they found the non-social and social sound conditions more difficult than the no sound condition, and autistic participants found the social sound condition more negative than neurotypical participants. However, decision-making and heart rate variability were similar for autistic and neurotypical participants across the sound conditions, suggesting that these measures may not have been sensitive enough to reflect the experiences the autistic participants reported. Further research should consider alternative measures to explore the experiences reported by autistic people to help us understand which specific aspects of the environment autistic people are sensitive to. This, in turn, may enable more specific and evidence-based autism-friendly changes to be made.

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3. Chen HY, Bohlen JF, Maher BJ. Molecular and Cellular Function of Transcription Factor 4 in Pitt-Hopkins Syndrome. Developmental neuroscience. 2021; 43(3-4): 159-67.

Transcription factor 4 (TCF4, also known as ITF2 or E2-2) is a type I basic helix-loop-helix transcription factor. Autosomal dominant mutations in TCF4 cause Pitt-Hopkins syndrome (PTHS), a rare syndromic form of autism spectrum disorder. In this review, we provide an update on the progress regarding our understanding of TCF4 function at the molecular, cellular, physiological, and behavioral levels with a focus on phenotypes and therapeutic interventions. We examine upstream and downstream regulatory networks associated with TCF4 and discuss a range of in vitro and in vivo data with the aim of understanding emerging TCF4-specific mechanisms relevant for disease pathophysiology. In conclusion, we provide comments about exciting future avenues of research that may provide insights into potential new therapeutic targets for PTHS.

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4. Deneubourg C, Ramm M, Smith LJ, Baron O, Singh K, Byrne SC, Duchen MR, Gautel M, Eskelinen EL, Fanto M, Jungbluth H. The spectrum of neurodevelopmental, neuromuscular and neurodegenerative disorders due to defective autophagy. Autophagy. 2022; 18(3): 496-517.

Primary dysfunction of autophagy due to Mendelian defects affecting core components of the autophagy machinery or closely related proteins have recently emerged as an important cause of genetic disease. This novel group of human disorders may present throughout life and comprises severe early-onset neurodevelopmental and more common adult-onset neurodegenerative disorders. Early-onset (or congenital) disorders of autophagy often share a recognizable « clinical signature, » including variable combinations of neurological, neuromuscular and multisystem manifestations. Structural CNS abnormalities, cerebellar involvement, spasticity and peripheral nerve pathology are prominent neurological features, indicating a specific vulnerability of certain neuronal populations to autophagic disturbance. A typically biphasic disease course of late-onset neurodegeneration occurring on the background of a neurodevelopmental disorder further supports a role of autophagy in both neuronal development and maintenance. Additionally, an associated myopathy has been characterized in several conditions. The differential diagnosis comprises a wide range of other multisystem disorders, including mitochondrial, glycogen and lysosomal storage disorders, as well as ciliopathies, glycosylation and vesicular trafficking defects. The clinical overlap between the congenital disorders of autophagy and these conditions reflects the multiple roles of the proteins and/or emerging molecular connections between the pathways implicated and suggests an exciting area for future research. Therapy development for congenital disorders of autophagy is still in its infancy but may result in the identification of molecules that target autophagy more specifically than currently available compounds. The close connection with adult-onset neurodegenerative disorders highlights the relevance of research into rare early-onset neurodevelopmental conditions for much more common, age-related human diseases.Abbreviations: AC: anterior commissure; AD: Alzheimer disease; ALR: autophagic lysosomal reformation; ALS: amyotrophic lateral sclerosis; AMBRA1: autophagy and beclin 1 regulator 1; AMPK: AMP-activated protein kinase; ASD: autism spectrum disorder; ATG: autophagy related; BIN1: bridging integrator 1; BPAN: beta-propeller protein associated neurodegeneration; CC: corpus callosum; CHMP2B: charged multivesicular body protein 2B; CHS: Chediak-Higashi syndrome; CMA: chaperone-mediated autophagy; CMT: Charcot-Marie-Tooth disease; CNM: centronuclear myopathy; CNS: central nervous system; DNM2: dynamin 2; DPR: dipeptide repeat protein; DVL3: disheveled segment polarity protein 3; EPG5: ectopic P-granules autophagy protein 5 homolog; ER: endoplasmic reticulum; ESCRT: homotypic fusion and protein sorting complex; FIG4: FIG4 phosphoinositide 5-phosphatase; FTD: frontotemporal dementia; GBA: glucocerebrosidase; GD: Gaucher disease; GRN: progranulin; GSD: glycogen storage disorder; HC: hippocampal commissure; HD: Huntington disease; HOPS: homotypic fusion and protein sorting complex; HSPP: hereditary spastic paraparesis; LAMP2A: lysosomal associated membrane protein 2A; MEAX: X-linked myopathy with excessive autophagy; mHTT: mutant huntingtin; MSS: Marinesco-Sjoegren syndrome; MTM1: myotubularin 1; MTOR: mechanistic target of rapamycin kinase; NBIA: neurodegeneration with brain iron accumulation; NCL: neuronal ceroid lipofuscinosis; NPC1: Niemann-Pick disease type 1; PD: Parkinson disease; PtdIns3P: phosphatidylinositol-3-phosphate; RAB3GAP1: RAB3 GTPase activating protein catalytic subunit 1; RAB3GAP2: RAB3 GTPase activating non-catalytic protein subunit 2; RB1: RB1-inducible coiled-coil protein 1; RHEB: ras homolog, mTORC1 binding; SCAR20: SNX14-related ataxia; SENDA: static encephalopathy of childhood with neurodegeneration in adulthood; SNX14: sorting nexin 14; SPG11: SPG11 vesicle trafficking associated, spatacsin; SQSTM1: sequestosome 1; TBC1D20: TBC1 domain family member 20; TECPR2: tectonin beta-propeller repeat containing 2; TSC1: TSC complex subunit 1; TSC2: TSC complex subunit 2; UBQLN2: ubiquilin 2; VCP: valosin-containing protein; VMA21: vacuolar ATPase assembly factor VMA21; WDFY3/ALFY: WD repeat and FYVE domain containing protein 3; WDR45: WD repeat domain 45; WDR47: WD repeat domain 47; WMS: Warburg Micro syndrome; XLMTM: X-linked myotubular myopathy; ZFYVE26: zinc finger FYVE-type containing 26.

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5. Figueiredo T. The Recurrence of Motor Tics Mediated by Oral Prednisolone Use in Autistic Children: A Case Report. Clinical neuropharmacology. 2021; 44(4): 145-7.

OBJECTIVES: This study aimed to report motor tics worsening by prednisolone acute treatment, despite the use of aripiprazole and clonidine. It was also aimed to discuss the mechanisms involved in neuropsychiatric adverse effects with the use of corticosteroids. METHODS: It was reported a 7-year-old boy patient with a history of autism spectrum disorder and motor tics. He has remitted motor tics with an association between aripiprazole and clonidine. However, was registered motor tics’ recurrence with acute use of prednisolone. CONCLUSIONS: The neuropsychiatric adverse effects mediated by corticosteroid use are low explored, mainly in pediatric clinical practice. The prednisolone prescription is widespread in childhood and, considering some vulnerable conditions to this type of adverse effects, is imperative.

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6. Huebschman JL, Davis MC, Tovar Pensa C, Guo Y, Smith LN. The fragile X mental retardation protein promotes adjustments in cocaine self-administration that preserve reinforcement level. The European journal of neuroscience. 2021; 54(3): 4920-33.

The fragile X mental retardation protein (FMRP), an RNA-binding protein, regulates cocaine-induced neuronal plasticity and is critical for the normal development of drug-induced locomotor sensitization, as well as reward-related learning in the conditioned place preference assay. However, it is unknown whether FMRP impacts behaviors that are used to more closely model substance use disorders. Utilizing a cocaine intravenous self-administration (IVSA) assay in Fmr1 knockout (KO) and wild-type (WT) littermate mice, we find that, despite normal acquisition and extinction learning, Fmr1 KO mice fail to make a normal upward shift in responding during dose-response testing. Later, when given access to the original acquisition dose under increasing fixed ratio (FR) schedules of reinforcement (FR1, FR3, and FR5), Fmr1 KO mice earn significantly fewer cocaine infusions than WT mice. Importantly, similar deficits are not present in operant conditioning using a palatable food reinforcer, indicating that our results do not represent broad learning or reward-related deficits in Fmr1 KO mice. Additionally, we find an FMRP target, the activity-regulated cytoskeleton-associated protein (Arc), to be significantly reduced in synaptic cellular fractions prepared from the nucleus accumbens of Fmr1 KO, compared with WT, mice following operant tasks reinforced with cocaine but not food. Overall, our findings suggest that FMRP facilitates adjustments in drug self-administration behavior that generally serve to preserve reinforcement level, and combined with our similar IVSA findings in Arc KO mice may implicate Arc, along with FMRP, in behavioral shifts that occur in drug taking when drug availability is altered.

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7. Kehinde F, Nagrodzki J, Clay F, Wilkinson P. Narrative Matters: ‘Who decides what a meaningful life is?’ Life, Animated – a refreshing insight into an autistic person’s life. Child and adolescent mental health. 2021; 26(3): 281-3.

Life, Animated (2016), directed by Roger Ross Williams is a documentary that centres around the life of Owen Suskind; an autistic person. In recent decades, the media has become a powerful tool that has been used to typify and inform public opinion surrounding autism. This article analyses the portrayal of autism in Life, Animated and draws out important learning points for clinicians, families, service users and the public.

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8. Kemeny B, Burk S, Hutchins D, Gramlich C. Therapeutic Riding or Mindfulness: Comparative Effectiveness of Two Recreational Therapy Interventions for Adolescents with Autism. Journal of autism and developmental disorders. 2021: 1-25.

Therapeutic riding (THR) and HeartMath (HM) mindfulness-based interventions have promise for reducing stress in adolescents with autism spectrum disorder. In three 10-week periods, this study compared THR, HM, and control on salivary cortisol, self-reported stress, parent-reported social responsiveness, and heart-rate variability. This crossover design included 27 participants (12-21 years) randomly assigned to order of intervention. Findings suggest that HM and THR manualized protocols are equally beneficial in decreasing cortisol levels immediately following a session, but HM sessions had more impact on heart-rate variability. There was no significant effect on follow-up cortisol levels within a week after either intervention, but THR had more impact on decreasing some self-reported stressors.

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9. Liu S, Yan Z, Huang Y, Zheng W, Deng Y, Zou Y, Xie H. A case of White-Sutton syndrome arising from a maternally-inherited mutation in POGZ. Psychiatric genetics. 2021; 31(4): 135-9.

POGZ is located on chromosome 1q21.3, encoding a pogo transposable element-derived protein with a zinc finger cluster. White-Sutton syndrome (WHSUS, OMIM:616364) is a genetic disorder resulting from de novo heterozygous pathogenic variants in POGZ, which manifests as intellectual disability, autism spectrum disorder, specific facial features and other phenotypic spectra. To date, a total of twenty-one de novo POGZ mutations in WHSUS have been reported. Here we report the identification of a novel missense variant in the coding region of the POGZ gene (c.4042G>C), which occurred in a 15-year-old male and his mother with WHSUS. We describe their clinical features and compare them with clinical data of patients with WHSUS from the literature. Our finding broadens the spectrum of POGZ mutations and provides a good example of precision medicine through the combination of exome sequencing and clinical testing.

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10. Maes P, Stercq F, Kissine M. Attention to intentional versus incidental pointing gestures in young autistic children: An eye-tracking study. Journal of experimental child psychology. 2021; 210: 105205.

Whereas a reduced tendency to follow pointing gestures is described as an early sign of autism, the literature on response to joint attention indicates that autistic children perform better when a point is added to other social cues such as eye gaze. The purpose of this study was to explore pointing processing in autism when it is the only available cue and to investigate whether autistic children discriminate intentional pointing gestures from incidental pointing gestures. Eye movements of 58 autistic children (48 male) and 61 typically developing children (36 male) aged 3-5 years were recorded as the children were watching videos of a person uttering a pseudoword and pointing intentionally with one hand and incidentally with the other hand. After 3 s, two different potential referents for the pseudoword gradually emerged in both pointed-at corners. In comparison with typically developing children, autistic children’s fixations were significantly farther away from both pointed-at zones. Upon hearing a novel word, typically developing children shifted their visual attention toward the zone pointed intentionally. This trend did not emerge in the group of autistic children regardless of their level of vocabulary. Autistic children, independently of their level of language, pay little attention to pointing when no other social cues are available and fail to discriminate intentional pointing gestures from incidental ones. They seem to grasp neither the spatial nor the social value of pointing.

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11. Sefik E, Purcell RH, Walker EF, Bassell GJ, Mulle JG. Convergent and distributed effects of the 3q29 deletion on the human neural transcriptome. Translational psychiatry. 2021; 11(1): 357.

The 3q29 deletion (3q29Del) confers high risk for schizophrenia and other neurodevelopmental and psychiatric disorders. However, no single gene in this interval is definitively associated with disease, prompting the hypothesis that neuropsychiatric sequelae emerge upon loss of multiple functionally-connected genes. 3q29 genes are unevenly annotated and the impact of 3q29Del on the human neural transcriptome is unknown. To systematically formulate unbiased hypotheses about molecular mechanisms linking 3q29Del to neuropsychiatric illness, we conducted a systems-level network analysis of the non-pathological adult human cortical transcriptome and generated evidence-based predictions that relate 3q29 genes to novel functions and disease associations. The 21 protein-coding genes located in the interval segregated into seven clusters of highly co-expressed genes, demonstrating both convergent and distributed effects of 3q29Del across the interrogated transcriptomic landscape. Pathway analysis of these clusters indicated involvement in nervous-system functions, including synaptic signaling and organization, as well as core cellular functions, including transcriptional regulation, posttranslational modifications, chromatin remodeling, and mitochondrial metabolism. Top network-neighbors of 3q29 genes showed significant overlap with known schizophrenia, autism, and intellectual disability-risk genes, suggesting that 3q29Del biology is relevant to idiopathic disease. Leveraging « guilt by association », we propose nine 3q29 genes, including one hub gene, as prioritized drivers of neuropsychiatric risk. These results provide testable hypotheses for experimental analysis on causal drivers and mechanisms of the largest known genetic risk factor for schizophrenia and highlight the study of normal function in non-pathological postmortem tissue to further our understanding of psychiatric genetics, especially for rare syndromes like 3q29Del, where access to neural tissue from carriers is unavailable or limited.

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12. Stantic M, Brewer R, Duchaine B, Banissy MJ, Bate S, Susilo T, Catmur C, Bird G. The Oxford Face Matching Test: A non-biased test of the full range of individual differences in face perception. Behavior research methods. 2022; 54(1): 158-73.

Tests of face processing are typically designed to identify individuals performing outside of the typical range; either prosopagnosic individuals who exhibit poor face processing ability, or super recognisers, who have superior face processing abilities. Here we describe the development of the Oxford Face Matching Test (OFMT), designed to identify individual differences in face processing across the full range of performance, from prosopagnosia, through the range of typical performance, to super recognisers. Such a test requires items of varying difficulty, but establishing difficulty is problematic when particular populations (e.g., prosopagnosics, individuals with autism spectrum disorder) may use atypical strategies to process faces. If item difficulty is calibrated on neurotypical individuals, then the test may be poorly calibrated for atypical groups, and vice versa. To obtain items of varying difficulty, we used facial recognition algorithms to obtain face pair similarity ratings that are not biased towards specific populations. These face pairs were used as stimuli in the OFMT, and participants were required to judge whether the face images depicted the same individual or different individuals. Across five studies the OFMT was shown to be sensitive to individual differences in the typical population, and in groups of both prosopagnosic individuals and super recognisers. The test-retest reliability of the task was at least equivalent to the Cambridge Face Memory Test and the Glasgow Face Matching Test. Furthermore, results reveal, at least at the group level, that both face perception and face memory are poor in those with prosopagnosia, and are good in super recognisers.

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13. Suhrheinrich J, Melgarejo M, Root B, Aarons GA, Brookman-Frazee L. Implementation of school-based services for students with autism: Barriers and facilitators across urban and rural districts and phases of implementation. Autism : the international journal of research and practice. 2021; 25(8): 2291-304.

The law requires that schools use evidence-based practices to educate students with autism spectrum disorder. However, these practices are often not used, or are not used correctly in school programs. Understanding barriers and facilitators of use of evidence-based practices in schools will help improve the implementation process. This study uses focus groups to characterize how school-based providers representing urban or rural school districts perceive barriers and facilitators for implementing new practices for students with autism spectrum disorder. Guiding questions include the following: (1) Are contextual factors perceived as barriers or facilitators and how do these vary by district location? and (2) What are the key factors impacting implementation across the Exploration, Preparation, Implementation, and Sustainment phases? Focus group participants (n = 33) were service providers to children with autism spectrum disorder from urban- and rural-located school districts. Several personnel-related themes (attitudes and buy-in, knowledge and skills, staffing, and burnout) were shared by participants representing both urban and rural districts. However, some personnel-related themes and organizational factors were unique to rural or urban districts. For example, themes related to system and organizational factors (leadership approval, support and expectations, district structure, competing priorities, time for effective professional development, litigation and due process, and materials and resources) differed between the district locations. This project serves as an initial step in identifying implementation strategies that may improve the use of evidence-based practices in schools.

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14. Wu Y, Zhong X, Lin Y, Zhao Z, Chen J, Zheng B, Li JJ, Fletcher JM, Lu Q. Estimating genetic nurture with summary statistics of multigenerational genome-wide association studies. Proceedings of the National Academy of Sciences of the United States of America. 2021; 118(25).

Marginal effect estimates in genome-wide association studies (GWAS) are mixtures of direct and indirect genetic effects. Existing methods to dissect these effects require family-based, individual-level genetic, and phenotypic data with large samples, which is difficult to obtain in practice. Here, we propose a statistical framework to estimate direct and indirect genetic effects using summary statistics from GWAS conducted on own and offspring phenotypes. Applied to birth weight, our method showed nearly identical results with those obtained using individual-level data. We also decomposed direct and indirect genetic effects of educational attainment (EA), which showed distinct patterns of genetic correlations with 45 complex traits. The known genetic correlations between EA and higher height, lower body mass index, less-active smoking behavior, and better health outcomes were mostly explained by the indirect genetic component of EA. In contrast, the consistently identified genetic correlation of autism spectrum disorder (ASD) with higher EA resides in the direct genetic component. A polygenic transmission disequilibrium test showed a significant overtransmission of the direct component of EA from healthy parents to ASD probands. Taken together, we demonstrate that traditional GWAS approaches, in conjunction with offspring phenotypic data collection in existing cohorts, could greatly benefit studies on genetic nurture and shed important light on the interpretation of genetic associations for human complex traits.

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15. Yang CY, Hung YC, Cheng KH, Ling P, Hsu KS. Loss of CC2D1A in Glutamatergic Neurons Results in Autistic-Like Features in Mice. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 2021; 18(3): 2021-39.

Biallelic loss-of-function mutations in Coiled-coil and C2 domain containing 1A (CC2D1A) cause autosomal recessive intellectual disability, sometimes comorbid with other neurodevelopmental disabilities, such as autism spectrum disorder (ASD) and seizures. We recently reported that conditional deletion of Cc2d1a in glutamatergic neurons of the postnatal mouse forebrain leads to impaired hippocampal synaptic plasticity and cognitive function. However, the pathogenic origin of the autistic features of CC2D1A deficiency remains elusive. Here, we confirmed that CC2D1A is highly expressed in the cortical zones during embryonic development. Taking advantage of Cre-LoxP-mediated gene deletion strategy, we generated a novel line of Cc2d1a conditional knockout (cKO) mice by crossing floxed Cc2d1a mice with Emx1-Cre mice, in which CC2D1A is ablated specifically in glutamatergic neurons throughout all embryonic and adult stages. We found that CC2D1A deletion leads to a trend toward decreased number of cortical progenitor cells at embryonic day 12.5 and alters the cortical thickness on postnatal day 10. In addition, male Cc2d1a cKO mice display autistic-like phenotypes including self-injurious repetitive grooming and aberrant social interactions. Loss of CC2D1A also results in decreased complexity of apical dendritic arbors of medial prefrontal cortex (mPFC) layer V pyramidal neurons and increased synaptic excitation/inhibition (E/I) ratio in the mPFC. Notably, chronic treatment with minocycline rescues behavioral and morphological abnormalities, as well as E/I changes, in male Cc2d1a cKO mice. Together, these findings indicate that male Cc2d1a cKO mice recapitulate autistic-like phenotypes of human disorder and suggest that minocycline has both structural and functional benefits in treating ASD.

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