Alterations in hippocampal network oscillations and theta–gamma coupling arise before Aβ overproduction in a mouse model of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by memory impairments. Brain oscillatory activity is critical for cognitive function and is altered in AD patients. Recent evidence suggests that accumulation of soluble amyloid-beta (Aβ) induces reorganization of hippocampal networks. However, whether fine changes in network activity might be present at very early stages, before Aβ overproduction, remains to be determined. We therefore assessed whether theta and gamma oscillations and their cross-frequency coupling, which are known to be essential for normal memory function, were precociously altered in the hippocampus. Electrophysiological field potential recordings were performed using complete hippocampal preparations in vitro from young transgenic CRND8 mice, a transgenic mouse model of AD. Our results indicate that a significant proportion of 1-month-old TgCRND8 mice showed robust alterations of theta-gamma cross-frequency coupling in the principal output region of the hippocampus, the subiculum. In addition we showed that, compared to controls, these mice expressed negligible levels of Aβ. Finally, these network alterations were not due to genetic factors as 15-day-old animals did not exhibit theta-gamma coupling alterations. Thus, initial alterations in hippocampal network activity arise before Aβ accumulation and may represent an early biomarker for AD.

Hippocampal network dynamics in response to α7 nACh receptors activation in amyloid-β overproducing transgenic mice

“…For the first time we report that these mice showed significantly decreased power of gamma oscillation, reduced theta-phase gammaamplitude coupling, and less preferential locking of gamma power to the phase of theta when compared to their WT counterparts during stimulation-induced hippocampal oscillations. In particular, we have observed a significant deficiency in the coupling of theta phase with the high gamma band, which is in accordance with observations made in hippocampal slice preparations from APP mutant TgCRND8 mice (Goutagny et al, 2013).…”

“…In heat-maps, there are two visibly distinct bands of coupling between theta and gamma in WT mice: low gamma (30 -55 Hz), and high gamma (65 -95 Hz). These bands correspond to functionally distinct frequency bands in hippocampal oscillations previously observed in vitro (Goutagny et al, 2013), and in vivo in behaving mice (Schomburg et al, 2014). TG mice showed suggestively lower coupling in low gamma-band (p = 0.0624; df = 30; t = 1.94, two-tailed t-test) and significantly lower coupling in high gamma-band (p = 0.0174; df = 30; t = 2.52, two-tailed t-test), (Fig.…”

Cortical network oscillations in Alzheimer's disease: insights from rodent models

“…Coupling between theta phase and gamma amplitude in the hippocampus, plays a key role in human [25] and rodent [26][27][28] learning and memory functions. Recently Goutagny et al found marked impairments in CFC in the theta-gamma bands in young TgCRND8 mice that express a double mutant form of APP, although neither theta nor gamma frequency amplitude was altered [29]. These results also suggest that human studies may reveal more consistent abnormalities in patients with AD by assessing more specific features of network activity such as theta-gamma CFC.…”

Modulation of hippocampal neuronal network oscillations by α7 nACh receptors

“…PAC between theta and gamma in the hippocampus has been implicated in information consolidation [10], learning [75], and memory [76]. In the rodent hippocampus, multiple, functionally distinct frequency bands in the gamma range have been recognized, although not strictly defined and sometimes overlapping, as slow (30 -50 Hz), midfrequency (50 -90 Hz), and fast (90 -140 Hz) gamma as being modulated by theta rhythm [10,77,78].…”

“…Further studies are warranted to determine if α7 nAChR agonists could enhance theta phase -gamma amplitude coupling in non-anesthetized mice, particularly during performing cognitive tasks. Since elicited hippocampal theta power and theta -gamma coupling are diminished in transgenic animal models capturing Aβ overproduction of Alzheimer's disease [67,77], it would be interesting to see how α7 nAChR agonists or other potential treatments could influence these dysfunctional mechanisms.…”