Neurexin-neuroligin trans-syanptic interaction in learning and memory

Abstract

The symptoms of autism first occur at the age when the birth and migration of neurons have been already completed in the brain. Therefore, it is likely that autism arises from disturbances in the remodeling and stabilization of synaptic connections between neurons, rather than from their initial formation. Thus, critical insights into the cellular and molecular mechanisms that underlie autism can be obtained by studying the effects that autism-implicated genes have on learning-induced changes in strength and structure of synaptic connections between neurons as well as the stabilization of these changes.

Thus, we propose to investigate the role of two autism-implicated genes, neurexin and neuroligin, in learning-induced changes in strength and structure of synaptic connections between neurons and the stabilization of these changes. Towards that goal, we will use two complementary animal models of learning with which we have extensive experience: (1) The gill-withdrawal reflex in Aplysia, which undergoes a simple form of learned-fear, long-term sensitization. The neural circuit that underlies the gill-withdrawal reflex can be reconstituted in dissociated cell culture allowing the analysis of the memory for behavioral sensitization to be reduced to the cellular and molecular level. We have found Aplysia genes corresponding to human neurexin and neuroligin and will investigate the role of these autism-implicated genes in learning and memory storage at the level of individual, identified synaptic connections. (2) The amygdala, a region in the brain involved in fear memory. There is strong evidence for a direct causal link between changes in the strength of synaptic connections in the amygdala and a simple behavioral paradigm, auditory fear conditioning. The amygdala has been found consistently to be affected in individuals with autism. We will investigate how acute suppression of endogenous neuroligin in the mouse amygdala affects the learning-induced changes in synaptic connections and the animal behavior.

Investigator

• Eric R. Kandel