Alterations to synaptic function and connectivity in area CA3 of the hippocampus in mouse models of mental retardation [electronic resource]

Down Syndrome and Fragile X Syndrome are disorders of mental retardation that are characterized by cognitive impairments and changes to other physical characteristics. A goal in the study of these diseases has been to understand the mechanisms that underlie the cognitive impairments present in these two disorders of mental retardation. A great deal of effort has been made to study synaptic function and structure in these disorders of mental retardation in order to determine whether there are any alterations present. Alterations to synaptic structure and function present during these disorders may give insight to the neural basis of the cognitive impairments that are characteristic of this disorder of mental retardation. An area of the brain that may be affected by these disorders is the hippocampus. This area of the brain has been extensively studied for its role in memory and alterations to synaptic function and structure may underlie some of the memory deficits present in these disorders of mental retardation. Both Down Syndrome patients and Fragile X Syndrome patients have deficits in their performance on memory tests. Down Syndrome patients also have a reduction in the number of neurons present in the hippocampus (Carlesimo et al., 1997). Fragile X Syndrome patients had structural abnormalities in the hippocampus including an enlargement of ventricular spaces (Jakala et al., 1997). Synaptic function and structure in the hippocampus of mouse models of Down Syndrome and Fragile X Syndrome were studied in order to determine this region of the brain was affected. Electrophysiology recordings in area CA3 of the hippocampus of the Ts65Dn Down Syndrome mouse model indicated there were disruptions to synaptic connectivity, decreases in excitatory and inhibitory synaptic transmission, and also a reduction in intrinsic interneuron activity. Imaging studies of CA3 in the Ts65Dn mouse did not show alterations to the number of synapses or structure of synapses suggesting that the alterations found with electrophysiology recordings are the result of functional changes to synapses. Electrophysiology study of the hippocampus in mouse models of Fragile X Syndrome has shown that inhibitory function was generally intact but that excitatory axons from neurons that lacked the Fragile X Mental Retardation Protein (FMRP) were less competitive at forming synapses in a mosaic expression system of the Fmr1 gene the lack of which causes the disease. These studies indicate that alterations to synaptic structure and function are present in the hippocampus of these mouse models of mental retardation. The differences however, were not the same in Down Syndrome and Fragile X Syndrome mouse models. Nonetheless, it is possible that the changes to synaptic function found in both of these mouse models leads to altered network function in the hippocampus which may, in turn, be the underlying cause of the memory deficits present in these disorders of mental retardation. The data presented in these studies indicate that the study of these mouse models of mental retardation can give insight to alterations caused by these disorders of mental retardation which may also lead to the development of new treatments.

Keywords: Molecular and Cellular Physiology.
Advisor: Madison Daniel V.
Goodman Miriam Beth advisor. Thesis advisor
Huguenard John advisor. Thesis advisor
MacIver M. Bruce (Murdo Bruce) advisor. Thesis advisor