Decreased parvalbumin and somatostatin neurons in medial prefrontal cortex in BRINP1-KO mice

Kobayashi, Miwako; Hayashi, Yuichi; Fujimoto, Yuko; Matsuoka, Isao

doi:10.1016/j.neulet.2018.06.050

Cited by 18 publications

(10 citation statements)

References 25 publications

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“…This is a similar phenotype to the one found in PV knockout mice (67). Conversely, decreased numbers of PV positive cells are found in other models of ASD, namely Cntnap2 -/-, Shank1 -/-, Shank3B -/-, and Brinp3 -/- (68)(69)(70)(71). Based on this evidence, a recent review by Filice and colleagues proposed the "Parvalbumin Hypothesis of Autism Spectrum Disorder", in which down-regulation of parvalbumin expression leads to altered neuronal function and abnormal neurotransmitter release, in addition to increasing reactive oxygen species production and dendritic branching (72).…”

Section: Discussionsupporting

confidence: 77%

Tsc1 haploinsufficiency leads to Pax2 dysregulation in the developing murine cerebellum

Serra

Stravs

Osório

et al. 2021

Preprint

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Tuberous sclerosis complex 1 (TSC1) is a tumour suppressor gene that inhibits the mechanistic target of rapamycin (mTOR) pathway. Mutations in TSC1 lead to a rare complex disorder of the same name, in which up to 50% of patients present with autism spectrum disorder (ASD). ASD is a highly prevalent, early-onset neurodevelopmental disorder, characterized by social deficits and repetitive behaviours, although the type and severity of symptoms show wide variability across individuals. Amongst different brain areas proposed to play a role in the development of ASD, the cerebellum is commonly reported to be altered, and cerebellar-specific deletion of Tsc1 in mice is sufficient to induce an ASD-like phenotype. Given that the mTOR pathway is crucial for proper cell replication and migration, this suggests that dysregulation of this pathway, particularly during critical phases of cerebellar development, could contribute to the establishment of ASD. Here, we used a mouse model of TSC to investigate gene and protein expression during embryonic and early postnatal periods of cerebellar development. We found that, at E18 and P7, mRNA levels of the cerebellar inhibitory interneuron marker Pax2 were dysregulated. This was accompanied by changes in the expression of mTOR pathway-related genes and downstream phosphorylation of S6. Differential gene correlation analysis revealed dynamic changes in correlated gene pairs across development, with an overall loss of correlation between mTOR- and cerebellar-related genes in Tsc1 mutants compared to controls. We corroborated the genetic findings by characterizing the mTOR pathway and cerebellar development on protein and cellular levels with Western blot and immunohistochemistry. We found that Pax2-expressing cells were hypertrophic at E18 while, at P7, their number was increased and maturation into parvalbumin-expressing cells delayed. Our findings indicate that E18 and P7 are crucial time points in cerebellar development in mice that are particularly susceptible to mTOR pathway dysregulation.

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Section: Discussionsupporting

confidence: 77%

Tsc1 haploinsufficiency leads to Pax2 dysregulation in the developing murine cerebellum

Serra

Stravs

Osório

et al. 2021

Preprint

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“…Specially, recent studies reported that activation of pyramidal neurons in the medial prefrontal cortex (mPFC) that project to subcortical areas or inhibition of pyramidal neurons in the ventral hippocampus (vHIP) that project to nucleus accumbens impaired normal social behavior (Murugan et al, 2017;Brumback et al, 2017). Both human and rodent studies have suggested that GABAergic neurons, especially PV+ mPFC (PV+ neurons in mPFC) are essential for normal social behaviors (Hashemi et al, 2017;Kobayashi et al, 2018). The PV+ neuron defects could be observed in postmortem human brain tissue of patients with autism (Hashemi et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Ventral Hippocampal-Prefrontal Interaction Affects Social Behavior via Parvalbumin Positive Neurons in the Medial Prefrontal Cortex

Sun

et al. 2020

iScience

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Ventral hippocampus (vHIP) and medial prefrontal cortex (mPFC) are both critical regions for social behaviors. However, how their interactions affect social behavior is not well understood. By viral tracing, optogenetics, chemogenetics, and fiber photometry, we demonstrated that inhibition of vHIP or direct projections from vHIP to mPFC impaired social memory expression. Via rabies retrograde tracing, we found that all three major GABAergic neurons in mPFC received direct inputs from vHIP. Activation of parvalbumin positive (PV+) neurons in mPFC but not somatostatin positive (SST+) neurons can rescue the social memory impairment caused by vHIP inhibition. Furthermore, fiber photometry results demonstrated that social behaviors preferentially recruited PV+ neurons and inhibition of hippocampal neurons disrupted the activity of PV+ neurons during social interactions. These results revealed a new mechanism of how vHIP and mPFC regulate social behavior in complementarity with the existing neural circuitry mechanism.

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“…While in disorders such as ASD, schizophrenia, and possibly other neurodevelopmental disorders (e.g., attention deficit hyperactivity disorder, where GABAergic interneurons were found also to play a role [57], the importance of PVALB neurons for proper brain function is undisputed, much more needs to be learned about when and how impairment of these neurons' structure/function is occurring, subsequently leading to the phenotypic changes observed in vivo in animal models, as well as in affected patients.…”

Section: Resultsmentioning

confidence: 99%

Profiling parvalbumin interneurons using iPSC: challenges and perspectives for Autism Spectrum Disorder (ASD)

et al. 2020

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Autism spectrum disorders (ASD) are persistent conditions resulting from disrupted/altered neurodevelopment. ASD multifactorial etiology-and its numerous comorbid conditions-heightens the difficulty in identifying its underlying causes, thus obstructing the development of effective therapies. Increasing evidence from both animal and human studies suggests an altered functioning of the parvalbumin (PV)-expressing inhibitory interneurons as a common and possibly unifying pathway for some forms of ASD. PV-expressing interneurons (short: PVALB neurons) are critically implicated in the regulation of cortical networks' activity. Their particular connectivity patterns, i.e., their preferential targeting of perisomatic regions and axon initial segments of pyramidal cells, as well as their reciprocal connections, enable PVALB neurons to exert a fine-tuned control of, e.g., spike timing, resulting in the generation and modulation of rhythms in the gamma range, which are important for sensory perception and attention. New methodologies such as induced pluripotent stem cells (iPSC) and genome-editing techniques (CRISPR/Cas9) have proven to be valuable tools to get mechanistic insight in neurodevelopmental and/or neurodegenerative and neuropsychiatric diseases. Such technological advances have enabled the generation of PVALB neurons from iPSC. Tagging of these neurons would allow following their fate during the development, from precursor cells to differentiated (and functional) PVALB neurons. Also, it would enable a better understanding of PVALB neuron function, using either iPSC from healthy donors or ASD patients with known mutations in ASD risk genes. In this concept paper, the strategies hopefully leading to a better understanding of PVALB neuron function(s) are briefly discussed. We envision that such an iPSC-based approach combined with emerging (genetic) technologies may offer the opportunity to investigate in detail the role of PVALB neurons and PV during "neurodevelopment ex vivo."

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Decreased parvalbumin and somatostatin neurons in medial prefrontal cortex in BRINP1-KO mice

Cited by 18 publications

References 25 publications

Tsc1 haploinsufficiency leads to Pax2 dysregulation in the developing murine cerebellum

Tsc1 haploinsufficiency leads to Pax2 dysregulation in the developing murine cerebellum

Ventral Hippocampal-Prefrontal Interaction Affects Social Behavior via Parvalbumin Positive Neurons in the Medial Prefrontal Cortex

Profiling parvalbumin interneurons using iPSC: challenges and perspectives for Autism Spectrum Disorder (ASD)

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