Synaptic transmission in human ES cell-derived neurons: A potential cell replacement-model in the CNS.

Brain aging or head injury often leads to substantial levels of cognitive disability. In particular, loss of neurons in the temporal lobe of the brain, such as perirhinal and entorhinal cortices, is thought to be one of the earliest neuropathlogical changes in Alzheimer's disease. For example, atrophy of perirhinal and entorhinal cortices, the areas affected earliest and most severely by the abnormal protein fragments (amyloid) and fibers (neurofibrillary tangles), is correlated with the severity of Alzheimer's disease. These neuropathological changes cannot repair themselves in mature central nervous system. Therefore, neuronal replacement or protection may be a potential therapy for neurodegeneration or neuronal death in the central nervous system (CNS). Strategies by which the CNS can be repaired following injury and/or degenerative disorder is, therefore, one of the major concerns in neuroscience at the present time. Recently, embryonic stem (ES) cells, derived from the inner cell mass of the blastocyst, can either self-renew or differentiate into any of the cell types found in the mature organism. The choice of self-renewal or differentiation is dependent on the micro-environment of the stem cell. Animal model studies have demonstrated that multipotent neuronal stem cells or progenitor cells can differentiate to neurons or glia in vitro. Thus, the proposed study will aim to establish an in-vitro model for cell replacement in the CNS. The study will test whether implanted ES cells are capable of functional integration into host neuronal circuitry in the perirhinal cortex. The perirhinal cortex is at the top of the sensory processing hierarchy, and involves visual recognition memory. Recognition memory requires judgement concerning prior occurrence. For example, to recognise a person in the street you might recollect information about them such as their name or where you previously met. Normally, the ability to discriminate what is novel, what is familiar or what has occurred recently is an effortless task. Judgements of prior occurrence, such as the recognition memory process, are important for everyday human life. However, loss of recognition memory is a major symptom of amnesia and early Alzheimer's disease. Using stem-cell biology and in-vitro electrophysiology, the proposed study will 1. characterize excitatory and inhibitory synaptic transmission in human ES cell derived neurons; 2. investigate the ability of ES cell-derived neurons to form synapses with host neuronal circuitry. The proposed study will establish a simple model for the cell replacement of lost or damaged neurons in the CNS, which may eventually enhance our understanding of the treatment methods available in neuro-degenerative disorders.

Our preliminary study has established that human embryonic stem cells (hES) cell can be differentiated into neurons. In addition, hES cells can be cultured in rat brain slices and express neuronal-like morphology and electro-physiological function. Therefore, the study will aim to establish an in-vitro model for the functional integration of human ES cell within host neuronal circuitry in the rat brain slice. Specifically, we will investigate (1) whether ES cell-derived neurons develop essential properties of a functional neuron and can integrate into host neural networks in perirhinal cortex slices and (2) whether grafted neurons can induce activity-dependent long-term synaptic plasticity which has been hypothesised as a cellular model of learning and memory in the CNS. Therefore, the proposed project will establish a model of hES cell-derived neuron replacement therapy and develop a potential therapeutical strategy for neurodegenerative disorders.