Surviving mossy cells enlarge and receive more excitatory synaptic input in a mouse model of temporal lobe epilepsy.

Numerous hypotheses of temporal lobe epileptogenesis have been proposed, and several involve hippocampal mossy cells. Building on previous hypotheses we sought to test the possibility that after epileptogenic injuries surviving mossy cells develop into super-connected seizure-generating hub cells. If so, they might require more cellular machinery and consequently have larger somata, elongate their dendrites to receive more synaptic input, and display higher frequencies of miniature excitatory synaptic currents (mEPSCs). To test these possibilities pilocarpine-treated mice were evaluated using GluR2-immunocytochemistry, whole-cell recording, and biocytin-labeling. Epileptic pilocarpine-treated mice displayed substantial loss of GluR2-positive hilar neurons. Somata of surviving neurons were 1.4-times larger than in controls. Biocytin-labeled mossy cells also were larger in epileptic mice, but dendritic length per cell was not significantly different. The average frequency of mEPSCs of mossy cells recorded in the presence of tetrodotoxin and bicuculline was 3.2-times higher in epileptic pilocarpine-treated mice as compared to controls. Other parameters of mEPSCs were similar in both groups. Average input resistance of mossy cells in epileptic mice was reduced to 63% of controls, which is consistent with larger somata and would tend to make surviving mossy cells less excitable. Other intrinsic physiological characteristics examined were similar in both groups. Increased excitatory synaptic input is consistent with the hypothesis that surviving mossy cells develop into aberrantly super-connected seizure-generating hub cells, and soma hypertrophy is indirectly consistent with the possibility of axon sprouting. However, no obvious evidence of hyperexcitable intrinsic physiology was found. Furthermore, similar hypertrophy and hyper-connectivity has been reported for other neuron types in the dentate gyrus, suggesting mossy cells are not unique in this regard. Thus, findings of the present study reveal epilepsy-related changes in mossy cell anatomy and synaptic input but do not strongly support the hypothesis that mossy cells develop into seizure-generating hub cells.

A 15-day course of donepezil modulates spectral EEG dynamics related to target auditory stimuli in young, healthy adult volunteers.

OBJECTIVE: To identify possible electroencephalographic (EEG) markers of donepezil's effect on cortical activity in young, healthy adult volunteers at the group level. METHODS: Thirty subjects were administered a daily dose of either 5mg donepezil or placebo for 15days in a double-blind, randomized, cross-over trial. The electroencephalogram during an auditory oddball paradigm was recorded from 58 scalp electrodes. Current source density (CSD) transformations were applied to EEG epochs. The event-related potential (ERP), inter-trial coherence (ITC: the phase consistency of the EEG spectrum) and event-related spectral perturbation (ERSP: the EEG power spectrum relative to the baseline) were calculated for the target (oddball) stimuli. RESULTS: The donepezil and placebo conditions differed in terms of the changes in delta/theta/alpha/beta ITC and ERSP in various regions of the scalp (especially the frontal electrodes) but not in terms of latency and amplitude of the P300-ERP component. CONCLUSION: Our results suggest that ITC and ERSP analyses can provide EEG markers of donepezil's effects in young, healthy, adult volunteers at a group level. SIGNIFICANCE: Novel EEG markers could be useful to assess the therapeutic potential of drug candidates in Alzheimer's disease in healthy volunteers prior to the initiation of Phase II/III clinical studies in patients.

Early Development of Symptomatic Drugs in AD: A Systematic Review of the Use of Biomarkers.

Pharmacological therapies currently marketed for Alzheimer's disease (AD) are only symptomatic and show limited effects in terms of clinical benefit. Thus, the development of new symptomatic drugs remains essential. However the dramatic increase in costs associated with drug development together with the poor number of emerging drugs highlights how crucial it is to accelerate the findings aiming to bringing new drugs to market. In this respect, optimization of the development process by integrating, at early stage, reliable biomarkers able to predict clinical benefit in phase III clinical trials may help. The improvement of certain techniques such as imaging and electrophysiological methods has led to a more accurate assessment of the brain's physiological impact of pharmacological treatments used to alleviate symptoms in AD patients. This review aims to gather the main findings from clinical studies where the effect of anti-dementia drugs were assessed in healthy volunteers and AD patients through one or several such biomarkers (electroencephalography (EEG), magnetic resonance imaging (MRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT)). Overall, evidence presented in this review suggests that various biomarkers associated with key impairments observed in AD were sensitive to acetylcholinesterase inhibitors (AChE-I) medication and memantine with a good correlation with enhancement of cognitive performance. In most of the reviewed studies, only one kind of biomarker was used. Among these, deficits in quantitative EEG profile, P300 latency, and regional brain activity measured by either functional MRI (fMRI) during face encoding and working memory task or by PET/SPECT have been shown to be reversed by anti-dementia drugs. It is therefore suggested that a single biomarker approach would be limited and not be sufficiently predictive to extensively assess the potential of a new symptomatic drug. Hence, it appears that a combination approach with the use of a panel of biomarkers rather than a single biomarker may be more appropriate to establish a good correlation between the disease and therapeutic intervention.