Development of the Prefrontal Cortex in NF-1 Mouse Models
Abstract
NF-1 is the most common form of autosomal dominant neurodevelopmental disorder, affecting 1 in ~3,000 individuals. Loss of NF1 results in prolonged activation of Ras and enhanced activation of downstream signaling cascades, including ERK/MAPK and PI3K pathways. In recent years, neurobehavioral abnormalities associated with the CNS have been gradually recognized as common symptoms in NF-1, including deficits in learning, motor, executive, and social functions. However, we know little about the mechanisms underlying the pathogenesis of these neurobehavioral symptoms. Clinical studies have revealed common abnormalities in brain structures and functional connectivity. These abnormalities were thought to underlie the pathogenesis of neurobehavioral symptoms in NF-1. The prefrontal cortex (PFC) is a key cortical structure involved in executive and social functions. Brain imaging studies suggest the involvement of PFC in social deficits in NF-1. Increased functional connectivity in NF-1 patients and enlargement of PFC in NF-1 mouse models were shown to negatively associate with social performance. The anatomical identify of PFC is directed by a signaling center that exerts its function through ERK/MAPK and PI3K pathways. Since loss of NF1 results in enhanced activation ERK/MAPK and PI3K pathways, we predict that Nf1 deficiency, which leads to enhanced ERK/MAPK and PI3K activation, may drive the expansion of PFC, as seen in both NF-1 patient and mouse models. Volumetric increase in PFC may lead to an increase in neuronal numbers and a subsequent increase in connectivity from the PFC to the amygdala and other subcortical structures. In fact, enhanced PFC connectivity to the amygdala is sufficient to induce social deficits, as demonstrated in additional mouse autism models with macrocephaly. In this proposal, we present a novel concept that defects abnormalities at brain structural, circuitry, and functional levels in NF-1 are contributed by improper formation of anatomically and functionally distinct brain structures. We hypothesize that Nf1 deficiency results in aberrant PFC specification and subsequent neural circuit malformation. We propose to quantitatively determine the effect of Nf1 deficiency on cortical subdomain specification using histological approaches and determine the cell-type composition of the PFC in both mono- and bi-allelic Nf1-inactivated mice. We will thoroughly investigate the effect of Nf1 deficiency on the formation of long-range cortical projections using both anterograde and retrograde neuronal circuit tracing approaches. We speculate that NF1 is critical for the development of distinct brain structures and the establishment of connectivity. Execution of this proposed study will vastly advance our knowledge of the function of NF1 in brain development. Results should also direct new research directions toward understanding the mechanism underlying deficits in social and executive functions and the search for effective intervention.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910402
Entities
People
- Lei Xing
Organizations
- United States Army
- University of North Carolina at Chapel Hill