Hippocampal Unicellular Recordings and Hippocampal-dependent Innate Behaviors in an Adolescent Mouse Model of Alzheimer’s disease

Abstract

Transgenic mice have been used to make valuable contributions to the field of neuroscience and model neurological diseases. The simultaneous functional analysis of hippocampal cell activity combined with hippocampal dependent innate task evaluations provides a reliable experimental approach to detect fine changes during early phases of neurodegeneration. To this aim, we used a merge of patch-clamp with two hippocampal innate behavior tasks. With this experimental approach, whole-cell recordings of CA1 pyramidal cells, combined with hippocampal-dependent innate behaviors, have been crucial for evaluating the early mechanism of neurodegeneration and its consequences. Here, we present our protocol for ex vivo whole-cell recordings of CA1 pyramidal cells and hippocampal dependent innate behaviors in an adolescent (p30) mice.

Circuitry and Synaptic Dysfunction in Alzheimer’s Disease: A New Tau Hypothesis

“…We also found that this reduction in the induction of epileptic activity correlated with pTau's MD accumulation in PCs [ 92 ]. Collectively, our results provide support for the alternative role of pTau protein during normal physiological conditions and early stages of AD development [ 7 , 13 , 14 , 92 , 93 ]. Importantly, it was reported that during the early stage of AD development, phosphorylation of Tau protein at its site Thr205 alleviated A β -induced neuronal death and provided protection from excitotoxicity [ 16 ].…”

“…Thus, from the classical point of view, all the data argued so far could favor the existence of a toxic cascade of A β 42-pTau/synaptic damage/network dysfunction. However, we firmly believe that our data, along with recently published data, will help to unveil a new hypothesis in which Tau phosphorylated near the MD could have a protective role during the early stages of AD development [ 13 – 16 , 29 , 92 , 93 ]. One molecular basis for this alternative hypothesis is that pTau protein at MD sites is physiologically located at the synaptic terminals [ 13 , 14 , 29 ].…”

“…It has to be remembered, the prevalence rates of seizures are significantly increased in patients with AD [ 95 – 97 ]. In fact, we confirmed this by challenging p30 triple transgenic AD mice with the potassium channel blocker 4-aminopyridine, a potent proepileptic drug [ 92 , 93 ]. We found that the p30 triple-transgenic AD mice exhibited a dramatic reduction in seizure-like activity after the 4-aminopyridine application [ 92 , 93 ].…”

“…In fact, we confirmed this by challenging p30 triple transgenic AD mice with the potassium channel blocker 4-aminopyridine, a potent proepileptic drug [ 92 , 93 ]. We found that the p30 triple-transgenic AD mice exhibited a dramatic reduction in seizure-like activity after the 4-aminopyridine application [ 92 , 93 ]. We also found that this reduction in the induction of epileptic activity correlated with pTau's MD accumulation in PCs [ 92 ].…”

“…Furthermore, Tau oligomers isolated from human AD patients produced an inhibition of the hippocampal LTP and induced memory dysfunction in rodents [ 91 ]. In our hands, we found that PCs and PV+ cells in p30 triple-transgenic AD mice accumulate pTau at MD sites and that this accumulation correlated with changes in hippocampal oscillatory activity [ 92 , 93 ]. Taken together, the latest evidence supports pTau accumulation in PCs and interneurons as an essential event that contributes to firing instability and, therefore, to brain network alterations, especially during very early stages of disease progression.…”