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Common Pathophysiology in Multiple Mouse Models of Pitt-Hopkins Syndrome
Courtney Thaxton1,2, Alexander D Kloth1,2, Ellen P Clark1,2
1Department of Cell Biology and Physiology.
Abstract:
Mutations or deletions of the transcription factor TCF4 are linked to Pitt-Hopkins syndrome (PTHS) and schizophrenia, suggesting that the precise pathogenic mutations dictate cellular, synaptic, and behavioral consequences. Here, we generated two novel mouse models of PTHS, one that mimics the most common pathogenic TCF4 point mutation (human R580W, mouse R579W) and one that deletes three pathogenic arginines, and explored phenotypes of these lines alongside models of pan-cellular or CNS-specific heterozygous Tcf4 disruption. We used mice of both sexes to show that impaired Tcf4 function results in consistent microcephaly, hyperactivity, reduced anxiety, and deficient spatial learning. All four PTHS mouse models demonstrated exaggerated hippocampal long-term potentiation (LTP), consistent with deficits in hippocampus-mediated behaviors. We further examined R579W mutant mice and mice with pan-cellular Tcf4 heterozygosity and found that they exhibited hippocampal NMDA receptor hyperfunction, which likely drives the enhanced LTP. Together, our data pinpoint convergent neurobiological features in PTHS mouse models and provide a foundation for preclinical studies and a rationale for testing whether NMDAR antagonists might be used to treat PTHS.SIGNIFICANCE STATEMENT Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder associated with TCF4 mutations/deletions. Despite this genetic insight, there is a need to identify the function of TCF4 in the brain. Toward this goal, we developed two mouse lines, including one harboring the most prevalent pathogenic point mutation, and compared them with two existing models that conditionally delete Tcf4 Our data identify a set of overlapping phenotypes that may serve as outcome measures for preclinical studies of PTHS treatments. We also discovered penetrant enhanced synaptic plasticity across mouse models that may be linked to increased NMDA receptor function. These data reveal convergent neurobiological characteristics of PTHS mouse models and support the further investigation of NMDA receptor antagonists as a possible PTHS treatment.
Insights
New mouse models reveal that TCF4 gene dysfunction in Pitt-Hopkins syndrome (PTHS) causes microcephaly, hyperactivity, and learning deficits. Enhanced hippocampal synaptic plasticity, linked to NMDA receptor overactivity, was observed across models, suggesting potential therapeutic targets.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Mutations in the transcription factor TCF4 are associated with neurodevelopmental disorders like Pitt-Hopkins syndrome (PTHS) and schizophrenia.
- The precise cellular and behavioral consequences of specific TCF4 mutations remain incompletely understood.
- There is a need to elucidate the function of TCF4 in the brain to develop effective treatments for PTHS.
Purpose of the Study:
- To generate and characterize novel mouse models of PTHS, including one mimicking the common R580W point mutation.
- To investigate the neurobiological and behavioral phenotypes resulting from impaired TCF4 function in the central nervous system (CNS).
- To identify convergent neurobiological features across different PTHS mouse models for potential therapeutic strategies.
Main Methods:
- Generation of two novel mouse models for PTHS: one with a point mutation (R579W) and one with deletion of pathogenic arginines in Tcf4.
- Phenotypic analysis of these novel models alongside existing pan-cellular and CNS-specific heterozygous Tcf4 disruption models in both sexes.
- Assessment of behavioral outcomes (microcephaly, hyperactivity, anxiety, spatial learning) and electrophysiological measurements (hippocampal long-term potentiation, NMDA receptor function).
Main Results:
- All four PTHS mouse models exhibited consistent microcephaly, hyperactivity, reduced anxiety, and impaired spatial learning.
- Exaggerated hippocampal long-term potentiation (LTP) was observed across all PTHS mouse models, correlating with behavioral deficits.
- R579W mutant and pan-cellular Tcf4 heterozygous mice showed hippocampal NMDA receptor hyperfunction, likely driving the enhanced LTP.
Conclusions:
- Impaired TCF4 function leads to convergent neurobiological and behavioral phenotypes in PTHS mouse models.
- Enhanced hippocampal synaptic plasticity, mediated by NMDA receptor hyperfunction, is a key feature of these PTHS models.
- The findings support the investigation of NMDA receptor antagonists as a potential therapeutic approach for Pitt-Hopkins syndrome.
