Information processing in the nervous system depends upon the electrical signal propagation along the neuron, and chemical and electrical signal propagation across neurons, referred to as synaptic transmission. Neurons constantly modify their molecular content to change their excitability and synaptic efficacy in order to process and store information in the network. Dysregulation of neuron excitability and synaptic efficacy is often manifested in neurological and psychiatric disorders, and thought to underlie some of the cognitive impairments and dysfunctions often seen in these diseases. Proteins are the key mediators of these processes and the prime targets for pharmacological interventions. Although the molecular components of these physiological phenomena were worked out in pioneering work, the precise function and molecular interplay is in most cases still elusive. With the combination of molecular manipulations in single neurons and a profound analysis of the electrophysiological properties, we want to dissect the molecular machinery in unprecedented precision.
Molecular mechanisms of NMDA receptor dependent synaptic plasticity
Activity-dependent changes in synaptic strength at glutamatergic synapses are considered to be the fundamental process in information processing and storage in the brain. This contributes directly to the development of neural circuit and experience-dependent behavioral plasticity including learning and memory. Many forms of plasticity existing in the brain can modify synaptic efficacy. One prominent model for activity-dependent synaptic plasticity is the NMDA receptor (NMDAR) dependent LTP and LTD (referred as LTP an LTD thereafter), which is mainly studied at hippocampal Schaffer collateral CA3-CA1 synapses. The hippocampus also plays a fundamental role in some forms of learning and memory, and has been implicated in a number of neurological and psychiatric disorders, including epilepsy, Alzheimer’s disease, and schizophrenia. Thus, understanding the mechanism underlying LTP and LTD may afford great insight in how synapses can be modified by experience. We will use lentivirus-mediated gene silencing and molecular replacement approaches to test how postsynaptic proteins regulate synaptic AMPAR function and how signaling specificity is achieved during the process of LTP and LTD.
Role of Calcium homeostasis in synaptic plasticity and learning
Calcium (Ca2+) influx via membrane receptors and ion channels is essential in these processes, translating extracellular events into intracellular signaling cascades, through Ca2+-calmodulin sensitive processes. Calmodulin binds to Ca2+ and is ubiquitously expressed in neurons. There are small neuronal proteins known to interact with calmodulin, and regulate the affinity of calmodulin for Ca2+ binding. Changes in these calmodulin binding proteins will presumably influence the downstream signaling pathways that are important for synaptic plasticity and learning and memory. One example is neurogranin whose levels change in response to behavioral, environmental, and hormonal stimulation in rodent models and under pathological conditions in humans. The neurogranin gene has been associated with neurological and neuropsychiatric disorders including schizophrenia and mental retardation. We have evidence suggesting that the activity-dependent translation of neurogranin serves as a key positive modulator of neural plasticity and learning via shifting the threshold of neural plasticity. We are currently using virus-mediated gene transfer to manipulate the levels and the activity-dependent translation of neurogranin and test the functional impact on synaptic plasticity and learning. Our study will help understand the function and regulation of neurogranin important for calcium homeostasis in health and diseases, and may provide therapeutic substrate for pharmacological interventions for schizophrenia patients.