Transgenic Engineering of Cholinesterases: Tools for Exploring Cholinergic Responses.
Abstract
The long-term objective of the research in the laboratory is to understand the molecular and cellular mechanisms that mediate the coupling of short-term changes in cholinergic neurotransmission to long-term consequences in motor, cognitive and autonomous functions. To study the pathways by which cholinergic inputs control neuritic and synaptic cytoarchitecture and determine changes in downstream-regulated genes, we have developed transgenic and antisense models which enable gain- and loss-of-function modulation in several acetylcholinesterase (AChE) variants. These led to the observation that AChE expression is essential for growth and affects synaptic development through its catalytic function, core protein and variable-termini domains. In transgenic mice, we found that overproduction alters expression of the neuronal circuitry-related members of the neurexin gene family and causes late onset, progressive deterioration in dendrite branching, neuromotor and cognitive faculties. Using hippocampal brain slices and an in vivo stress protocol, we demonstrated that both acute stress and exposure to anti-cholinesterases disrupt the blood-brain barrier and promote long-lasting changes in cholinergic gene expression. Currently, cosmid sequencing and genotyping studies are being employed to explore the association of intragenic and neighboring sequences with regulation of the expression of the AChE gene, which is essential for responses to drugs and scavenging of poisons.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 1998
- Accession Number
- ADA363559
Entities
People
- Hermona Soreq
Organizations
- Hebrew University of Jerusalem