Acute Effects of Two Different Species of Amyloid-β on Oscillatory Activity and Synaptic Plasticity in the Commissural CA3-CA1 Circuit of the Hippocampus

Recent evidence indicates that soluble amyloid-β (Aβ) species induce imbalances in excitatory and inhibitory transmission, resulting in neural network functional impairment and cognitive deficits during early stages of Alzheimer’s disease (AD). To evaluate the in vivo effects of two soluble Aβ species (Aβ25-35 and Aβ1-40) on commissural CA3-to-CA1 (cCA3-to-CA1) synaptic transmission and plasticity, and CA1 oscillatory activity, we used acute intrahippocampal microinjections in adult anaesthetized male Wistar rats. Soluble Aβ microinjection increased cCA3-to-CA1 synaptic variability without significant changes in synaptic efficiency. High-frequency CA3 stimulation was rendered inefficient by soluble Aβ intrahippocampal injection to induce long-term potentiation and to enhance synaptic variability in CA1, contrasting with what was observed in vehicle-injected subjects. Although soluble Aβ microinjection significantly increased the relative power of γ-band and ripple oscillations and significantly shifted the average vector of θ-to-γ phase-amplitude coupling (PAC) in CA1, it prevented θ-to-γ PAC shift induced by high-frequency CA3 stimulation, opposite to what was observed in vehicle-injected animals. These results provide further evidence that soluble Aβ species induce synaptic dysfunction causing abnormal synaptic variability, impaired long-term plasticity, and deviant oscillatory activity, leading to network activity derailment in the hippocampus.

Synaptic Variability Introduces State-Dependent Modulation of Excitatory Spinal Cord Synapses

The relevance of neuronal and synaptic variability remains unclear. Cellular and synaptic plasticity and neuromodulation are also variable. This could reflect state-dependent effects caused by the variable initial cellular or synaptic properties or direct variability in plasticity-inducing mechanisms. This study has examined state-dependent influences on synaptic plasticity at connections between excitatory interneurons (EIN) and motor neurons in the lamprey spinal cord. State-dependent effects were examined by correlating initial synaptic properties with the substance P-mediated plasticity of low frequency-evoked EPSPs and the reduction of the EPSP depression over spike trains (metaplasticity). The low frequency EPSP potentiation reflected an interaction between the potentiation of NMDA responses and the release probability. The release probability introduced a variable state-dependent subtractive influence on the postsynaptic NMDA-dependent potentiation. The metaplasticity was also state-dependent: it was greater at connections with smaller available vesicle pools and high initial release probabilities. This was supported by the significant reduction in the number of connections showing metaplasticity when the release probability was reduced by high Mg2+Ringer. Initial synaptic properties thus introduce state-dependent influences that affect the potential for plasticity. Understanding these conditions will be as important as understanding the subsequent changes.

Modulation of Cellular and Synaptic Variability in the Lamprey Spinal Cord

Variability is increasingly recognized as a characteristic feature of cellular, synaptic, and network properties. While studies have traditionally focused on mean values, significant effects can result from changes in variance. This study has examined cellular and synaptic variability in the lamprey spinal cord and its modulation by the neuropeptide substance P. Cellular and synaptic variability differed in different types of cell and synapse. Substance P reduced the variability of subthreshold locomotor-related depolarizations and spiking in motor neurons during network activity. These effects were associated with a reduction in the variability of spiking in glutamatergic excitatory network interneurons and with a reduction in the variance of excitatory interneuron-evoked excitatory postsynaptic potentials (EPSPs). Substance P also reduced the variance of postsynpatic potentials (PSPs) from crossing inhibitory and excitatory interneurons, but it increased the variance of inhibitory postsynpatic potentials (IPSPs) from ipsilateral inhibitory interneurons. The effects on the variance of different PSPs could occur with or without changes in the PSP amplitude. The reduction in the variance of excitatory interneuron-evoked EPSPs was protein kinase A, calcium, and N-methyl-d-aspartate (NMDA) dependent. The NMDA dependence suggested that substance P was acting postsynaptically. This was supported by the reduced variability of postsynaptic responses to glutamate by substance P. However, ultrastructural analyses suggested that there may also be a presynaptic component to the modulation, because substance P reduced the variability of synaptic vesicle diameters in putative glutamatergic terminals. These results suggest that cellular and synaptic variability can be targeted for modulation, making it an additional source of spinal cord plasticity.