# Disruption of spinal circuit early development after silencing En1/Foxp2 interneurons

> **NIH NIH R21** · EMORY UNIVERSITY · 2023 · $430,375

## Abstract

ABSTRACT
Rhythmic spontaneous activity episodes, known as spontaneous network activity (SNA), occur throughout the
central nervous system (CNS) at the time in which the first synaptic connections are established. During this
time an early connectome is form and it is through later maturation and refinement of these early connections
that adult synaptic circuitries with mature functionalities emerge. Therefore, the early development of this first
connectivity is critical for later adult functional networks and when genetic or environmental factors disrupt SNA
the resulting adult circuits are malformed and dysfunctional. For example, SNA mechanisms are disturbed in
fetal alcohol spectrum disorders resulting in anomalous circuit development in the hippocampus. Similarly,
many neurodevelopmental disorders like those in the autism spectrum display associated motor deficits in the
newborn. SNA has been intensely studied in some CNS regions (retina, visual pathways, hippocampus) and
the exact cellular interactions involved, the assembly and disassembly of the SNA network and its significance
for maturation of correctly connected adult circuits are well known. Surprisingly, less is known about SNA in
spinal cord motor circuits, despite this being an early model for the study of SNA mechanisms. Currently, the
literature offers contradictory conclusions on the exact types of neurons involved in the SNA spinal network
and the significance of SNA for spinal circuit development remains unexplored. These are critical gaps in our
knowledge given the large number of motor syndromes in newborns with unknown etiology. This exploratory
proposal stems from the serendipitous finding of profound ataxia and limb discoordination in mouse pups in
which spinal inhibitory interneurons expressing the transcription factors engrailed 1 (En1) and forkhead box P2
(Foxp2) were chronically silenced throughout embryonic development. This suggests major dysfunction in
adult spinal motor circuits controlling limbs and preliminary results suggest disruption of early SNA in the
embryo. This genetic model could therefore offer a new entry point to interrogate cellular mechanisms in the
network driving SNA in the spinal cord (Aim 1) and the consequences of SNA dysfunction for the later
organization of key spinal motor circuits (Aim 2). For the second aim we will use as model the most basic of
motor circuits composed by extensor and flexor motoneurons, Ia reciprocal inhibitory interneurons (many of
which are En1-Foxp2) and Renshaw cells. This circuit displays a well-defined organization of specific
connections that has been extensively studied for many years and therefore offers an unambiguous model to
test the role of SNA in establishing specific connectivity. We hypothesize that its basic organization will be
disrupted by anomalous early SNA given that the principal interneurons involved in the SNA network (Renshaw
cells and Ia inhibitory interneurons) are also participants in this adu...

## Key facts

- **NIH application ID:** 10752857
- **Project number:** 1R21NS134172-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** FRANCISCO J ALVAREZ
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $430,375
- **Award type:** 1
- **Project period:** 2023-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10752857

## Citation

> US National Institutes of Health, RePORTER application 10752857, Disruption of spinal circuit early development after silencing En1/Foxp2 interneurons (1R21NS134172-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10752857. Licensed CC0.

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