Year: 2013
Type: dissertation
Abstract: In the central nervous system, neurons are connected through local contacting structures called synapses. The initial contacts between axons and dendrites undergo changes in morphology and protein composition, and differentiate into fully functional synapses. Precise regulation on synapse formation is essential for normal brain functioning. Cell adhesion molecules are the key regulators during this process, by connecting the membranes of synapses and initiating signaling cascades that mediate synapse formation. A neuron-specific cell adhesion molecule ICAM-5 (telencephalin) controls immune responses by suppressing T-cell activation or by mediating neuron-microglia interaction. On the other hand, ICAM-5 is so far the only identified CAM that slows synaptic development. Deletion of ICAM-5 from mice leads to accelerated synapse formation, enhanced synaptic capacity, and improved memory and learning. Clinically, changes in ICAM-5 levels are associated with various diseases, such as acute encephalitis, epilepsy, and Alzheimer s disease. The major goal of my thesis is to address the molecular mechanisms by which ICAM-5 regulates synapse formation as well as maturation of dendritic spines, the post-synaptic components of excitatory synapses. In my study, ICAM-5 was observed as a substrate for MMP-2 and -9. Activation NMDA receptors in neurons elevated the level of MMP activity, and subsequently induced ICAM-5 ectodomain cleavage, which in turn promoted spine maturation. In addition, I identified the pre-synaptic β1-integrins as counter-receptors for ICAM-5. This trans-synaptic interaction inhibited the MMP-induced ICAM-5 cleavage, and thereby prevented spine maturation. At the intracellular side, α-actinin, an actin cross-linking protein, was found as a binding partner for ICAM-5. This binding linked ICAM-5 to the actin cytoskeleton and was important for the membrane distribution of ICAM-5 and neurite outgrowth. The GluN1 subunit of the NMDAR is also known to bind to α-actinin. We found here that GluN1 and ICAM-5 competed for the same binding region in α-actinin. Activation of NMDAR changed α-actinin binding property to ICAM-5, resulting in α-actinin accumulation and actin reorganization. In conclusion, my thesis defines a novel, ICAM-5-dependent mechanism, which regulates synapse formation, spine maturation and remodeling.
Source: Työväentutkimus Vuosikirja
Author: Ning Lin
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2245960727