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Functional and synaptic deficits in cerebral cortical neurons in Alzheimer’s Disease model mice

Final Report Summary - AD SYNAPTIC DEFICITS (Functional and synaptic deficits in cerebral cortical neurons in Alzheimer's Disease model mice)

The effects of Alzheimer's Disease (AD) neuropathology on the function of neocortical neurons is not fully understood. AD is associated with a number of neuropathological features: plaques, tangles, and neuronal death. A central focus of AD research is the "amyloid hypothesis" (Hardy and Selkoe, 2002): that accumulation of amyloid-ß protein is a major cause of the cognitive dysfunction and dementia observed in AD patients. In addition, it has been suggested that plaque accumulation disrupts hypercolumnar organisation in the neocortex. Although some studies have shown alterations in synaptic function in cortical neurons in amyloid-ß transgenic mice, the effects of plaques on the function of the intact network remain unclear.

The goal of the present project was to study the specific effects of amyloid–ß on neocortical activity at the cellular and at the network level and find out how the neocortical functions are impaired. More specifically, we aimed at characterising the disruption of the somatosensory cortical organisation by correlating structural and functional changes induced by the presence of the amyloid–ß plaques.

In this study, we used the B6C3 mice that develop amyloid–ß plaques at earlier ages (> 6 months) as AD model strain and we have focused on the receptive fields of somatosensory cortical neurons responsive to whisker stimulation using in vivo intracellular recording. Histological staining has been used to provide structural information on the plaque location and their effects on the axonal/dendritic spatial organisation.

We found that the membrane potential dynamics of the neurons in plaque-burdened cortex differed from those of the nontransgenic controls with a clear disruption on a major collective pattern of electrical activity displayed by cortical circuits, namely Up/Down states. In plaque-burdened cortical circuits "broken" Up-states were observed as the durations of the depolarised Up states were often characterised by intermittent hyperpolarising events. Additionally, the occurrence of "aborted" Up-states, i. e. depolarising events in the Down state failing to induce Up state transitions, were significantly greater in plaque-burdened cortical neurons. This is an important result since changes in membrane potential dynamics have implications on the sensory information processing characteristics of the cortical network. We hypothesize that network failures ("broken" and "aborted" up-states) are induced by the distortion in the cortical structural organisation due to the plaque accumulation. These observations opened a new line of research in our group aimed at linking altered network dynamics to changes in synaptic input patterns and synchronous synaptic events.

In addition, similarly to the APP+ Sw Tg2576 mice that develop plaques by the age of 14 months, we found altered synaptic responses leading to distorted receptive fields of cortical neurons in B6C3 mice with significant plaque accumulation. This is a very important result since the measurements in two stains of transgenic mice that develop neuropathology at different ages show that the changes in neuronal activity are correlated with the pathology, rather than age. Since age is a risk factor in neurodegenerative disease, it is critical to distinguish between effects caused by normal aging and those caused by the disease process. This study has achieved that goal.

Neurons were recorded from the area of primary somatosensory cortex responsive to whisker deflection. In this area, the thalamic inputs to Layer IV are segregated into discrete areas, called barrels, which form the basis for the cortical columns. The neurons in Layers II/III of this area receive inputs from the principal whisker, as well as whiskers surrounding the principal input. Using this as a model system, we found that the responses to distal inputs (second-order surround whiskers) are more distorted by plaque-burdened cortex than inputs form the principal whisker. The major effect is the lowered contribution of the surround areas to the receptive field, indicating that the distortion of the sensory response increase with the distance traversed by the sensory afferents to the cortical column containing the neuron. The results of these experiments have important implications for Alzheimer's disease suggesting that the cortical spatial maps of the sensory environment are distorted.

In addition, since plaques and/or soluble amyloid-ß may have a direct effect on intrinsic electrophysiological properties (such as voltage-dependent conductances), we measured input-output relationships of cortical neurons from the barrel cortex of transgenic and control mice by injecting a series of positive and negative current pulses through the intracellular recording electrode and measuring the resulting voltage deflections. No apparent differences were observed in the I-V curves of the neurons from control and transgenic mice. These results, taken with those described above demonstrate that synaptic deficits, rather than changes in the intrinsic neuronal properties, are the origin of the altered neuronal responses in AD brain circuits.

A further finding was that the plaques distort the cortical structural organisation in the primary somatosensory cortex which is responsive to whisker deflection. In this area, the thalamic inputs to Layer IV are segregated into discrete areas called barrels, which form the basis for the cortical columns. Immunohistochemical studies on transgenic mouse cortical circuits with thioflavine-S revealed that the plaques distribute in barrels and even more frequently in the interbarrel septae. These data support the idea that horisontal spread of cortical information, i. e. from one receptive field to the adjacent ones, is affected by the presence of the plaques.

Next, we observed that the degree of neuritic curvature and dystrophy in the cortex is enhanced supporting the idea that amyloid-ß plaques impact neural system function by disrupting dendritic and axonal geometries, especially in the vicinity of dense core plaques.

Therefore, although we did not succeed in measurements at the level of the single synapse, we did succeed in measurements at the level of dendrites and axons, as well as subthreshold function.

All these results support the idea that the presence of amyloid-ß plaques disrupt the geometry and the structural organisation of the circuits with a direct impact on the ability of the circuits to propagate and process information determining possible network failures.

Taken together, these results have shown a significant deficit in synaptic function underlying changes in sensory properties of neurons in the neocortex in Alzheimer's Disease model mice. This is the first study showing such a deficit in relation to amyloid-ß plaques, providing significant support for the amyloid hypothesis of AD. In addition, we have separated the effects of the neuropathology from those associated with normal aging, which is a critical risk factor in the disease. This project has therefore increased our understanding of the morphological and physiological changes affecting neuronal structure and synaptic function in AD model animals, changes that may underlie some of the symptoms of Alzheimer's Disease.

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