Biology subjects

Philpot, B.

Publications and source records attributed to Philpot, B..

3 recordsLinked to original sources

bioRxiv2025

Juvenile reinstatement of TCF4 in Pitt-Hopkins syndrome model mice reveals a critical window for genetic intervention

Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by haploinsufficiency of TCF4 which encodes transcription factor 4. As PTHS therapeutics advance toward clinical trials, identifying the optimal timing for treatment is crucial. Our previous research demonstrated that restoring TCF4 during embryonic or neonatal stages, corresponding to prenatal or neonatal periods in humans, improved phenotypes in a PTHS mouse model (Kim et al., 2022). However, PTHS diagnosis generally occurs much later, when infants fail to reach developmental milestones and undergo genetic testing. This raises an essential question: can genetic therapeutics initiated at more clinically relevant time points retain effectiveness? Here, we examined whether reinstating TCF4 in juvenile PTHS model mice could reverse behavioral phenotypes, simulating a gene therapy. Our findings indicate that this delayed intervention largely fails to correct most phenotypes, except for a measure of cognitive function. These results reveal phenotype-specific plasticity and underscore a narrow, early critical window for effective treatment in PTHS. Our study also identifies the hippocampus as a potential target for PTHS therapeutics and suggests that while some cognitive functions may still retain therapeutic plasticity, reversing most core PTHS symptoms may require intervention during the very early postnatal, or potentially prenatal periods, in humans.

neuroscience↗

bioRxiv2021

Rescue of behavioral and electrophysiological phenotypes in a Pitt-Hopkins syndrome mouse model by genetic restoration of Tcf4 expression

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.

neuroscience↗

bioRxiv2020

The impact of interneurons on nonlinear synaptic integration in the neocortex

Excitatory inputs arriving at the dendrites of a neuron can engage active mechanisms that nonlinearly amplify the depolarizing currents. Interneuron-mediated inhibition can modulate this active process, in a subtype-dependent manner. For example, dendrite-targeting inhibition is hypothesized to increase the amplitude of synaptic input required to activate voltage-dependent nonlinear synaptic integration. To examine how inhibition influences active synaptic integration, we optogenetically manipulated the activity of two different subtypes of interneurons: dendrite-targeting somatostatin-expressing (SOM) and perisomatic-targeting parvalbumin-expressing (PV) interneurons. In acute slices of mouse primary visual cortex, electrical stimulation evoked nonlinear synaptic integration that depended on N-methyl-D-aspartate (NMDA) receptors. Optogenetic activation of SOM neurons in conjunction with electrical stimulation resulted in predominantly divisive inhibitory gain control, reducing the magnitude of the nonlinear response without affecting its threshold. PV activation, on the other hand, had a minimal effect on dendritic nonlinearities, resulting in a small subtractive effect. Furthermore, we found that mutual inhibition among SOM interneurons was strong and more prevalent than previously thought, while mutual inhibition among PV interneurons was minimal. These results challenge previous models of inhibitory modulation of active synaptic integration. The major effect of SOM inhibition is not a shift in threshold for activation of nonlinear integration, but rather a decrease the amplitude of the nonlinear response.

neuroscience↗