Transcription factor 4 is a class I basic helix-loop-helix transcription factor regulating gene expression. Altered TCF4 gene expression has been linked to non-syndromic intellectual disability, schizophrenia, and a severe neurodevelopmental disorder known as Pitt-Hopkins syndrome. An understanding of the cell types expressing TCF4 protein in the mouse brain is needed to help identify potential pathophysiological mechanisms and targets for therapeutic delivery in TCF4-linked disorders. Here we developed a novel green fluorescent protein reporter mouse to visualize TCF4-expressing cells throughout the brain. Using this TCF4 reporter mouse, we observed prominent expression of TCF4 in the pallial region and cerebellum of the postnatal brain. At the cellular level, both glutamatergic and GABAergic neurons express TCF4 in the cortex and hippocampus, while only a subset of GABAergic interneurons express TCF4 in the striatum. Among glial cell groups, TCF4 is present in astrocytes and immature and mature oligodendrocytes. In the cerebellum, cells in the granule and molecular layer express TCF4. Our findings greatly extend our knowledge of the spatiotemporal and cell type-specific expression patterns of TCF4 in the brain, and hence, lay the groundwork to better understand TCF4-linked neurological disorders. Any effort to restore TCF4 functions through small molecule or genetic therapies should target these brain regions and cell groups to best recapitulate TCF4 expression patterns.

Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by monoallelic mutation or deletion in the transcription factor 4 (TCF4) gene. Individuals with PTHS typically present in the first year of life with developmental delay and exhibit intellectual disability, lack of speech, and motor incoordination. There are no effective treatments available for PTHS, but the root cause of the disorder, TCF4 haploinsufficiency, suggests that it could be treated by normalizing TCF4 gene expression. Here, we performed proof-of-concept viral gene therapy experiments using a conditional Tcf4 mouse model of PTHS and found that postnatally reinstating Tcf4 expression in neurons improved anxiety-like behavior, activity levels, innate behaviors, and memory. Postnatal reinstatement also partially corrected EEG abnormalities, which we characterized here for the first time, and the expression of key TCF4-regulated genes. Our results support a genetic normalization approach as a treatment strategy for PTHS, and possibly other TCF4-linked disorders.

BackgroundThe concept of decision-making capacity (DMC) or competence remains controversial, despite widespread use. Risk-sensitive DMC assessment (RS-DMC)—the idea that the higher the risk involved in a decision, the greater the decisional abilities required for DMC—has been particularly controversial. We conducted a systematic, descriptive review of the arguments for and against RS-DMC to clarify the debate.MethodsWe searched PubMed/MEDLINE (National Library of Medicine), PsycInfo (American Psychological Association) and Philpapers, updating our search to February 15th, 2022. We targeted peer-reviewed publications in English that argue for or against RS-DMC. Two reviewers independently screened the publications and extracted data from each eligible manuscript.ResultsOf 41 eligible publications, 22 supported a risk-sensitive threshold in DMC assessment. Most arguments for RS-DMC rely on its intuitive appeal and practical merits. The arguments against RS-DMC primarily express concerns about paternalism and the seeming asymmetry between consent and refusal; critics of RS-DMC support epistemic, rather than substantive (i.e., variable threshold), risk-sensitivity; counterarguments responding to criticisms of RS-DMC address charges of paternalism and exhibit a notable variety of responses to the issue of asymmetry. Authors used a variety of frameworks regarding the definition of DMC, its elements, and its relation to decisional authority, and these frameworks were significantly associated with positions on RS-DMC. A limitation of our review is that the coding relies on judgment and interpretation.ConclusionThe review suggests that some of the debate about RS-DMC stems from differences in underlying frameworks. Most defenses of RS-DMC rely on its intuitive appeal, while most criticisms reflect concerns about paternalism or the asymmetry between consent and refusal. Defenses of RS-DMC respond to the asymmetry problem in a variety of ways. Further research is needed on the implications of underlying frameworks, the asymmetry problem, and the distinction between epistemic and substantive models of RS-DMC.

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