Insights into synaptic function from mouse models of human cognitive disorders

Abstract

Modern approaches to the investigation of the molecular mechanisms underlying human cognitive disease often include multidisciplinary examination of animal models engineered with specific mutations that spatially and temporally restrict expression of a gene of interest. This approach not only makes possible the development of animal models that demonstrate phenotypic similarities to their respective human disorders, but has also allowed for significant progress towards understanding the processes that mediate synaptic function and memory formation in the nondiseased state. Examples of successful mouse models where genetic manipulation of the mouse resulted in recapitulation of the symptomatology of the human disorder and was used to significantly expand our understanding of the molecular mechanisms underlying normal synaptic plasticity and memory formation are discussed in this article. These studies have broadened our knowledge of several signal transduction cascades that function throughout life to mediate synaptic physiology. Defining these events is key for developing therapies to address disorders of cognitive ability.

Keywords: Alzheimer’s disease; Angelman syndrome; Reelin; Rubinstein-Taybi syndrome; autism; hippocampus; knockout mouse; neurofibromatosis type 1; secretin; synaptic plasticity.

Figure 1. The hippocampal trisynaptic pathway and electrophysiology recording

The hippocampus consists of a trisynaptic pathway that can be maintained through acute lateral slicing of the mouse brain. Using this technique, the ex vivo slices can be artificially stimulated and recordings can be made across well-known sites of synaptic connections. The hippocampal DG receives major inputs from the EC through activation of the pp. (A) STIM of the pp can be recorded as an excitatory postsynaptic potential (EPSP) in the dendritic field of the DG. The granule cells of the DG synapse onto the dendrites of the pyramidal cells composing area CA3 via the mf. The pyramidal neurons of CA3 project to area CA1 via the SC synapses to the pyramidal neurons of area CA1. Presynaptic STIM of CA3 axons results in EPSPs in area CA1 recorded from either (B) the cell body layer or (C) dendritic fields of CA1. The primary output of the hippocampus is to the subiculum in area CA1, and subsequent signaling exits the hippocampus to the EC. DG: Dentate gyrus; EC: Entorhinal cortex; mf: Mossy fiber; pp: Perforant path; SC; Schaffer collateral; STIM: Stimulation.

Figure 2. Model of Reelin, apoE, neurofibromatosis 1, CBP, secretin and Ube3a at the synapse

The molecular machinery associated with signaling of Reelin, apoE, NF1, CBP, secretin and Ube3a are shown in the postsynaptic cell. Dotted lines are used to indicated transition through other signaling machinery not included (e.g., G-protein signaling). Individual pathways are color-coded and cross-talk is indicated by solid lines. Signaling through all six pathways ultimately affects synaptic function by the regulation of ion channels and/or by altering transcription, thereby modulating learning and memory. Genes, protein products and their associated cognitive disorders as discussed in the text are shown. AMPAR: AMPA receptor; ApoER2: ApoE receptor 2; CBP: CREB binding protein; Glu: Glutamate; NF1: Neurofibromatosis 1; NMDAR: N-methyl-D-aspartate receptor; Nt: Neurotransmitter; SR: Secretin receptor.