Reduction of Hippocampal Hyperactivity Improves Cognition in Amnestic Mild Cognitive Impairment

Abstract

Summary Elevated hippocampal activation is observed in conditions that confer risk for Alzheimer's disease, including amnestic mild cognitive impairment (aMCI). Studies in relevant animal models have indicated that over-activity in selective hippocampal circuits contributes to cognitive impairment. Here we tested the effect of reducing hippocampal activation in aMCI. Under placebo treatment, hippocampal activation in the dentate gyrus/CA3 was elevated in aMCI patients compared to a healthy control group. By using a low dose of the antiepileptic levetiracetam hippocampal activation in aMCI was reduced to a level that did not differ from the control group. Compared to aMCI memory performance under placebo, performance in the scanning task was significantly improved under drug treatment. Contrary to the view that greater hippocampal activation might serve a beneficial function, these results support the view that increased hippocampal activation in aMCI is a dysfunctional condition and that targeting excess hippocampal activity has therapeutic potential.

Hippocampal Neural Disinhibition Causes Attentional and Memory Deficits

“…Moreover, our findings support recent studies in humans and rodent models linking hippocampal overactivity and hyperexcitability to age-related memory deficits (Koh et al 2010;Bakker et al 2012;Davis et al 2014) and are consistent with the correlation of hippocampal overactivity with memory deficits in schizophrenia (Tregellas et al 2014). However, hippocampal neural disinhibition may facilitate hippocampal synaptic plasticity and, thereby, improve memory, if such disinhibition is finely and dynamically regulated by endogenous plasticity (Donato et al 2013) or if there is a pre-existing deficit due to increased neural inhibition (Fernandez et al 2007).…”

“…Our present findings in rats suggest that hippocampal neural disinhbition contributes to clinically relevant attentional and memory deficits. Furthermore, they support that causal relationships underly the recently reported correlations of hippocampal overactivity with both memory and attentional deficits in schizophrenia patients (Tregellas et al 2014) and the association of hippocampal overactivity with memory deficits in amnestic mild cognitive impairment (Bakker et al, 2012). …”

“…Given the close link between neural activity and metabolic activation (Sokoloff 1981), the enhanced hippocampal mutli-unit activity caused by acute GABA antagonism is consistent with the hippocampal metabolic overactivity characterizing early stages of these disorders (Schobel et al 2009;Bakker et al 2012;Huang and Mucke 2012).…”

“…This has recently been established for prefrontal GABA dysfunction (Gruber et al 2010;Enomoto et al 2011;Paine et al 2011;Pehrson et al 2013;Pezze et al 2014;Paine et al 2015;Tse et al 2015), and there is also evidence linking hippocampal neural disinhibition and overactivity to impaired hippocampus-dependent memory performance (Koh et al 2010;Murray et al 2011;Andrews-Zwilling et al 2012;Bakker et al 2012 ;Caputi et al 2012;Gilani et al 2014;Lovett-Barron et al 2014). Moreover, regional disinhibition, by causing aberrant drive of projections, may disrupt neural activity and cognitive processing in distal sites.…”

Potential of GABA-ergic cell therapy for schizophrenia, neuropathic pain, and Alzheimer׳s and Parkinson׳s diseases

“…Likewise, increased production or aggregation of Aβ interferes with interneuron function and leads to abnormal DG activity and cognitive impairments (Verret et al, 2012). Additionally, patients with mild cognitive impairment and young presymptomatic apoE4 carriers exhibit hippocampal hyperexcitability (Filippini et al, 2009;Yassa et al, 2010;Bakker et al, 2012). Thus, an excitatory-inhibitory imbalance in the hippocampus likely contributes to memory dysfunction in both aging and AD (Huang and Mucke, 2012).…”