Hilar GABAergic Interneuron Activity Controls Spatial Learning and Memory Retrieval

Abstract

BackgroundAlthough extensive research has demonstrated the importance of excitatory granule neurons in the dentate gyrus of the hippocampus in normal learning and memory and in the pathogenesis of amnesia in Alzheimer's disease (AD), the role of hilar GABAergic inhibitory interneurons, which control the granule neuron activity, remains unclear.Methodology and Principal FindingsWe explored the function of hilar GABAergic interneurons in spatial learning and memory by inhibiting their activity through Cre-dependent viral expression of enhanced halorhodopsin (eNpHR3.0)—a light-driven chloride pump. Hilar GABAergic interneuron-specific expression of eNpHR3.0 was achieved by bilaterally injecting adeno-associated virus containing a double-floxed inverted open-reading frame encoding eNpHR3.0 into the hilus of the dentate gyrus of mice expressing Cre recombinase under the control of an enhancer specific for GABAergic interneurons. In vitro and in vivo illumination with a yellow laser elicited inhibition of hilar GABAergic interneurons and consequent activation of dentate granule neurons, without affecting pyramidal neurons in the CA3 and CA1 regions of the hippocampus. We found that optogenetic inhibition of hilar GABAergic interneuron activity impaired spatial learning and memory retrieval, without affecting memory retention, as determined in the Morris water maze test. Importantly, optogenetic inhibition of hilar GABAergic interneuron activity did not alter short-term working memory, motor coordination, or exploratory activity.Conclusions and SignificanceOur findings establish a critical role for hilar GABAergic interneuron activity in controlling spatial learning and memory retrieval and provide evidence for the potential contribution of GABAergic interneuron impairment to the pathogenesis of amnesia in AD.

Hippocampal Neural Disinhibition Causes Attentional and Memory Deficits

“…Our finding, highlighting the importance of GABAergic inhibition for hippocampusdependent memory performance, converges with recent studies in mice reporting learning-related increase of hippocampal inhibitory synapses (Ruediger et al 2012) and impaired memory performance following disruption of hippocampal GABA neuron function by molecular-, opto-or pharmacogenetic approaches (Prut et al 2010;Murray et al 2011;Andrews-Zwilling et al 2012;Caputi et al 2012;Donato et al 2013;Gilani et al 2014;Lovett-Barron et al 2014;Engin et al 2015;Lee et al 2016). 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).…”

“…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.…”

Increased anxiety‐like behavior and selective learning impairments are concomitant to loss of hippocampal interneurons in the presymptomatic SOD1(G93A) ALS mouse model

“…In fact, the main reductions in PVi populations occurred before the onset of motor symptoms. It is known that the acquisition phase of spatial navigation learning is impaired when GABAergic interneurons in the hilus of the DG are inhibited (Andrews-Zwilling et al, 2012). Also, silencing the CA1 PVi affects spatial working memory but not reference memory, whereas both types of memories are disrupted when DG interneurons are silenced .…”

Dihydromyricetin Prevents Fetal Alcohol Exposure-Induced Behavioral and Physiological Deficits: The Roles of GABAA Receptors in Adolescence

“…Numerous studies have demonstrated impairment in various learning and memory tasks in adolescent and adult FAE rats, including hippocampal-mediated spatial reference memory [88][89][90][91][92][93]. Both DGCs and hilar GABAergic interneurons of the dentate gyrus were demonstrated to be integral neural substrates for spatial reference and spatial working memory [94][95][96][97].…”