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Since dendritic spines and excitatory synapses are lost in AD it is expected that both the distribution and functions of GABA B receptors are affected.
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Immunoelectron microscopic studies demonstrated an association of GABA B receptors with postsynaptic and presynaptic sites at excitatory synapses in the hippocampus, with a particularly high abundance in the dendritic spines of pyramidal cells 8, 27, 32, 53. Autoradiographic, in situ hybridisation and immunohistochemical studies showed that the hippocampus expresses a high-density of GABA B receptors 4, 6, 7, 12, 25, 32. Two subunits, GABA B1 and GABA B2, are required to form functional receptors 26, 37. GABA B receptors have modulatory actions on neuronal excitability and neurotransmitter release, and are involved in a number of physiological and pathophysiological processes 3, including AD. While alterations in the expression of GABA A receptor subunits in the AD hippocampus differ 28 alterations in GABA B receptor expression are less well understood and only recently it has been shown a direct molecular and functional link between APP and GABA B receptors 9, 45, 47. The neurotransmitter γ-aminobutyric acid (GABA) acts through GABA A and GABA B receptors to inhibit neurons 3, 13. Thus, N-methyl-D-aspartate (NMDA) receptors activation and removal of AMPA receptors have been implicated in AD-related synaptic dysfunctions 20, 59.
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Growing evidence supports that structural plasticity impairments on excitatory synapses are linked to a gross disruption of the glutamatergic system 36, 41, 55, 58, 59. The progressive increase in synapse loss correlates with cognitive decline and is proposed to underlie learning and memory deficits in AD 21.Īmyloid β (Aβ) has been implicated in the pathogenesis of AD by creating a microenvironment that damages the dendritic spines, which represent the major postsynaptic elements of excitatory synapses in the cerebral cortex 16, and are fundamental to memory formation, learning and cognition 30. The three major neuropathology hallmarks of AD are extracellular amyloid plaques containing amyloid β (Aβ) peptides derived from amyloid precursor protein (APP), neurofibrillary tangles of aggregated hyperphosphorylated tau in neurons and synapse loss 5. In particular, the CA1 hippocampal region is one of the most affected brain areas in AD, suffering a variety of neuronal alterations, including dendritic changes in pyramidal cells and pronounced loss of neurons 55, 56. Alzheimer's disease progression has been associated with a gradual damage in function and structure of the hippocampus, a vulnerable brain region involved in the memory formation and in the cognition. Our data demonstrate compartment- and age-dependent reduction of plasma membrane-targeted GABA B receptors in the CA1 region of the hippocampus, suggesting that this decrease might be enough to alter the GABA B-mediated synaptic transmission taking place in AD.Īlzheimer's disease (AD) is the most prevalent neurodegenerative disease in the elderly population. We further observed a decrease of membrane-targeted GABA B receptors in axon terminals contacting CA1 pyramidal cells. This reduction of plasma membrane GABA B1 was paralleled by a significant increase of the subunit at the intracellular sites. In contrast, immunoelectron microscopic techniques showed that the subcellular localization of GABA B1 subunit did not change significantly in APP/PS1 mice at 1 month of age, was significantly reduced in the stratum lacunosum-moleculare of CA1 pyramidal cells at 6 months of age and significantly reduced at the membrane surface of CA1 pyramidal cells at 12 months of age. Western blots and histoblots showed that the total amount of protein and the laminar expression pattern of GABA B1 were similar in APP/PS1 mice and in age-matched wild-type mice. By combining histoblots, western blots, immunohistochemistry and high-resolution immunoelectron microscopic methods for GABA B receptors, this study provides a quantitative description of the expression and the subcellular localization of GABA B1 in the hippocampus in a mouse model of AD at 1, 6 and 12 months of age. Despite numerous investigations about the processes required for the normal hippocampal functions, the neurotransmitter receptors involved in the synaptic deficits by which AD disables the hippocampus are not yet characterized.
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The hippocampus plays key roles in learning and memory and is a main target of Alzheimer's disease (AD), which causes progressive memory impairments.
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