Neurexin-neuroligin interaction in learning and memory

Autism arises in early childhood, during a period of intense learning when many of the brain's connections are modified by experience. Several autism-associated proteins also play important roles in memory formation.

To study the role of autism-associated proteins in the formation of memory, Eric Kandel, Yun-Beom Choi, Craig Bailey and their colleagues at Columbia University in New York used two model systems: (i) a simple form of learned fear in the sea slug, Aplysia californica, and (ii) the mouse amygdala, the brain region that controls fear memory. People with autism often have unusual responses to fear in new situations, a feature that correlates with abnormal activity in the amygdala.

The researchers found that two autism-associated proteins — neurexin on the transmitting nerve cell and neuroligin on the receiving nerve cell — are important for the induction and stabilization of changes in synaptic connections during learning in slugs1.

Kandel's team also started investigating candidate proteins that may regulate the translation of neurexin and neuroligin, such as FMRP. They found that FMRP in slugs is important for long-term inhibition, a cellular mechanism that underlies habituation2.

They also studied the binding partners of neurexin and neurologin, such as CASK, to determine the specific molecular cascades that are recruited by activation of this trans-synaptic signaling. These experiments revealed that CASK is important for learning in slugs.

Genetic suppression of neuroligin-1 in the mouse amygdala impaired both fear conditioning and learning-induced strengthening of synaptic connections. This led Kandel and his colleagues to investigate how acute suppression of neurexin-1-alpha in the mouse amygdala may affect learning-induced changes in synaptic connections and associated fear memory.