Synaptic and behavioral function of neuropsychiatric disorder-related genes, Cereblon and Lrrtm3

Abstract

The brain, the most complex organ in our body, generates our every behaviors and it is composed of numerous neurons. Neurons are connected and communicated each other, and this junctional space between two cells is called the synapse. There are many proteins in a neuron and around a synapse and these proteins are important for several functions in the brain such as a neuronal or synaptic development, maintaining these structures, or communication of the nervous system. If only one of them has a problem, this system abnormally works and it finally causes various brain diseases. Diseases induced by synaptic dysfunction are called the synaptopathy. To conquer synaptopathy, it is necessary to understand the original function of the genes or the proteins, that the mutation of them is found in human neuropsychiatric disorder patients, in a neuron or a synapse, and how the mutated products change normal function. These understandings not only can contribute to understand how the brain works but also will help to establish strategies for treatment of the neuropsychiatric disorders. Synaptic cell-adhesion molecules (CAMs) are necessary for connecting pre- and post-synaptic neurons at the synapse like a glue for normal neuronal or synaptic development and function. Leucine-rich repeat transmembrane proteins (LRRTMs) are recently identified synaptic cell-adhesion molecules and also contribute to the development and the function of excitatory synapse. The correlation between the mutation of these genes and some neuropsychiatric disorders are also reported. The LRRTM family is compose of four members, LRRTM1 to LRRTM4, but the molecular and cellular roles of LRRTM3 are not studied yet compared with others. On the other hand, there were some genetic studies and clinical case reports about the association between the mutation of LRRTM3 and Alzheimers disease (AD) or autism-spectrum disorders (ASDs). In chapter I, based on these background I studied the neuronal and synaptic function of LRRTM3 by using Lrrtm3 knockout (KO) mice. Intellectual disability (ID) is another common neuropsychiatric disorder, and recent studies have addressed this disorder as a synaptopathy. The mutation of gene cereblon (CRBN) was found from mild intellectual disability patients, and some additional studies were reported to reveal the correlation between the intellectual disability or developmental delay and the mutation of CRBN. CRBN that binds with other proteins to form CRL4CRBN E3 ubiquitin ligase complex acts as the substrate receptor by binding with target proteins such as  subunit of large-conductance calcium-activated potassium (BK) channel or  subunit of AMP kinase (AMPK). However, how CRBN regulates the neuronal function and how CRBN mutation causes cognitive deficits are still unknown. In chapter II, I studied the neuronal, synaptic and behavioral role of CRBN by using Crbn KO mice. These researches to reveal the neuronal, synaptic or behavioral roles of neuropsychiatric disorder-related genes not only are fundamental to understand these diseases but also will contribute to seek therapeutic plans.