Enhancing GABA Signaling during Middle Adulthood Prevents Age-Dependent GABAergic Interneuron Decline and Learning and Memory Deficits in ApoE4 Mice

Abstract

Apolipoprotein E4 (apoE4) is the major genetic risk factor for Alzheimer's disease (AD). However, the underlying mechanisms are still poorly understood. We previously reported that female apoE4 knock-in (KI) mice had an age-dependent decline in hilar GABAergic interneurons that correlated with the extent of learning and memory deficits, as determined by Morris water maze (MWM), in aged mice. Enhancing GABA signaling by treating aged apoE4-KI mice with the GABA A receptor potentiator pentobarbital (PB) for 4 weeks before and during MWM rescued the learning and memory deficits. Here, we report that withdrawal of PB treatment for 2 weeks before MWM abolished the rescue in aged apoE4-KI mice, suggesting the importance of continuously enhancing GABA signaling in the rescue. However, treating apoE4-KI mice during middle adulthood (9 -11 months of age) with PB for 6 weeks prevented age-dependent hilar GABAergic interneuron decline and learning and memory deficits, when examined at 16 month of age. These data imply that increasing inhibitory tone after substantial GABAergic interneuron loss may be an effective symptomatic, but not a disease-modifying, treatment for AD related to apoE4, whereas a similar intervention before substantial interneuron loss could be a disease-modifying therapeutic.

Early restoration of parvalbumin interneuron activity prevents memory loss and network hyperexcitability in a mouse model of Alzheimer’s disease

“…The decrease, and respective rescue, of both inhibitory and excitatory transmission might thus reflect a compensatory homeostatic network response to pathological alterations in interneuron activity [6,7]. In conclusion, while several studies have shown that memory loss and network dysfunction can be treated with positive modulators of GABAergic transmission [24,60,61], our data indicate that they may actually be prevented when hyperactive PV interneurons are targeted early.…”

Presynaptic proteins complexin-I and complexin-II differentially influence cognitive function in early and late stages of Alzheimer’s disease

“…The results reported here provide some support for the relevance of treatment strategies in animal models of Alzheimer’s disease directed at increasing inhibitory tone [13, 26, 27, 51]. Limited evidence suggests pharmacotherapies directly targeting components of the presynaptic molecular machinery such as levetiracetam (which interacts with the vesicular protein SV2) may be of benefit in Alzheimer’s disease through modulating inhibitory tone [16, 28, 30, 39, 52].…”

Histological characterization of interneurons in Alzheimer's disease reveals a loss of somatostatin interneurons in the temporal cortex

“…16,[27][28][29] By restoring GABA receptor signaling with pentobarbital following GABAergic interneuronal loss, memory and learning deficits were rescued in the apoE4-KI mice. 5 Also, the use of the neuroprotective peptide α-MSH attenuated GABAergic interneuron loss and improved cognition in the TgCRND8 mouse model of AD. 16 Repetitive activity in pyramidal neurons can drive SST interneurons into providing feedback inhibition.…”

“…These cells comprise the chandelier cells which innervate the axon initial segment, basket cells that target the soma of excitatory cells, and translaminar interneurons. 5 These interneurons are responsible for their fast-spiking activity and precise inhibitory control of pyramidal cell output. 6 Somatostatin (SST)expressing interneurons, the Martinotti and non-Martinotti cells, fire more randomly and gradually to stimulus targeting dendrites of excitatory neurons.…”

“…The learning and memory deficits that correlated with the age-dependent decline in SST interneurons in the apoE4-KI mouse model of AD were rescued following the restoration of GABA signaling using pentobarbital, a GABA A receptor enhancer. 5 Another mutated amyloid precursor protein (APP) familial mouse model of AD exhibited memory deficits and a reduction in GABArelated proteins and GABAergic interneurons as early as 4 months. 20 With APP known to play a role in GABAergic synaptic formations, by administering diazepam and correcting the APP function, an improvement in memory and also reduced Aβ accumulation was seen.…”