Treatment Strategies Targeting Excess Hippocampal Activity Benefit Aged Rats with Cognitive Impairment

Abstract

Excess neural activity in the CA3 region of the hippocampus has been linked to memory impairment in aged rats. We tested whether interventions aimed at reducing this excess activity would improve memory performance. Aged (24–28 mo-old) male Long-Evans rats were characterized in a spatial memory task known to depend on the functional integrity of the hippocampus, such that aged rats with identified memory impairment were used in a series of experiments. Over-expression of the inhibitory neuropeptide Y 13–36 in the CA3 via adeno-associated viral transduction was found to improve hippocampal-dependent long-term memory in aged rats that had been characterized with impairment. Subsequent experiments with two commonly used antiepileptic agents, sodium valproate and levetiracetam, similarly produced dose-dependent memory improvement in such aged rats. Improved spatial memory with low doses of these agents was observed in both appetitve and aversive spatial tasks. The benefits of these different modalities of treatment are consistent with the concept that excess activity in the CA3 region of the hippocampus is a dysfunctional condition that may play a key role underlying age-related impairment in hippocampal-dependent memory processes. Because increased hippocampal activation occurs in age-related memory impairment in humans as observed in functional neuroimaging, the current findings also suggest that low doses of certain antiepileptic drugs in cognitively impaired elderly humans may have therapeutic potential and point to novel targets for this indication.

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).…”

“…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

“…In rodent models, significant decreases in numbers of GABA-ergic interneurons are one of the conspicuous alterations seen in the aged hippocampus (Shetty and Turner, 1998;Stanley and Shetty, 2004;Shetty et al, 2009;Koh et al, 2010;Kuruba et al, 2011;Spiegel et al, 2013). Alterations in the function of GABA-ergic interneurons leads to increased neural activity in the CA3 region of the aged hippocampus, which contributes to memory dysfunction as the hyperactive CA3 pyramidal neurons are unable to encode new information in a pattern that is typically done in the young hippocampus (Wilson et al, 2003;Koh et al, 2010). This notion is supported by observations that overexpression of NPY (a neuromodulator released by a subclass of GABA-ergic neurons) in the hippocampal CA3 region, or treatment with low doses of valproate (an anti-epileptic drug that increases GABA-ergic neurotransmission), can improve hippocampal-dependent long-term memory in aged rats (Koh et al, 2010).…”

“…Alterations in the function of GABA-ergic interneurons leads to increased neural activity in the CA3 region of the aged hippocampus, which contributes to memory dysfunction as the hyperactive CA3 pyramidal neurons are unable to encode new information in a pattern that is typically done in the young hippocampus (Wilson et al, 2003;Koh et al, 2010). This notion is supported by observations that overexpression of NPY (a neuromodulator released by a subclass of GABA-ergic neurons) in the hippocampal CA3 region, or treatment with low doses of valproate (an anti-epileptic drug that increases GABA-ergic neurotransmission), can improve hippocampal-dependent long-term memory in aged rats (Koh et al, 2010). Decreased inhibitory neurotransmission likely also occurs in AD as brain concentrations of GABA and SST are reduced in the brain and the cerebrospinal fluid (Davies et al, 1980;Hardy et al, 1987;Seidl et al, 2001).…”

Neural stem cell- and neurogenesis-related gene expression profiles in the young and aged dentate gyrus

“…However, in the DG, the expression of Adora1 is low but is seen in isolated cells localized to the SGZ-GCL, the CA3c subregion, and the dentate hilus (based on Allen Brain Atlas). Increased expression of Adora1 in the aged DG may represent a compensatory reaction because aging is associated with increased hippocampal excitability (Koh et al 2010) and activation of adenosine A 1 receptors can reduce epileptiform activity and seizure-induced hippocampal damage (Hamil et al 2012). …”