Differential impacts on multiple forms of spatial and contextual memory in diazepam binding inhibitor knockout mice

Abstract

Learning and memory are fundamental processes that are disrupted in many neurological disorders including Alzheimer’s disease and epilepsy. The hippocampus plays an integral role in these functions, and modulation of synaptic transmission mediated by γ-aminobutyric acid (GABA) type-A receptors (GABAARs) impacts hippocampus-dependent learning and memory. The protein diazepam binding inhibitor (DBI) differentially modulates GABAARs in various brain regions, including hippocampus, and changes in DBI levels may be linked to altered learning and memory. The effects of genetic loss of DBI signaling on these processes, however, have not been determined. In these studies, we examined male and female constitutive DBI knockout mice and wild-type littermates to investigate the role of DBI signaling in modulating multiple forms of hippocampus-dependent spatial learning and memory. DBI knockout mice did not show impaired discrimination of objects in familiar and novel locations in an object location memory test, but did exhibit reduced time spent exploring the objects. Multiple parameters of Barnes maze performance, testing the capability to utilize spatial reference cues, were disrupted in DBI knockout mice. Furthermore, whereas most wild-type mice adopted a direct search strategy upon learning the location of the target hole, knockout mice showed higher rates of using an inefficient random strategy. In addition, DBI knockout mice displayed typical levels of contextual fear conditioning, but lacked a sex difference observed in wild-type mice. Together, these data suggest that DBI selectively influences certain forms of spatial learning and memory, indicating novel roles for DBI signaling in modulating hippocampus-dependent behavior in a task-specific manner.

The gliotransmitter ACBP controls feeding and energy homeostasis via the melanocortin system

“…More generally, it is important to mention that ACBP is expressed in several brain regions (e.g., amygdala, hippocampus) that are not commonly associated with the control of energy balance. Although the role of ACBP in these regions is still unclear, studies suggest that endogenous ACBP may play a role in social (56) and learning behavior (57). Importantly, we recently reported that astroglial ACBP deficiency does not affect anxiety in mice (31), ruling out the possibility that susceptibility to diet-induced obesity in ACBP GFAP KO mice is confounded by changes in anxiety-like behavior.…”

Molecular Basis of GABA Hypofunction in Adolescent Schizophrenia-Like Animals

“…What is more, we suggest GABA A R signaling in astrocytes could also be inhibited by downregulation of DBI. DBI selectively knockout mice has shown certain forms of impaired spatial learning and memory [ 62 ]. NMDARs express in a low abundance on astrocytes.…”

Infantile spasms‐linked Nedd4‐2 mediates hippocampal plasticity and learning via cofilin signaling

“…To first determine the associative learning and memory, we conducted the contextual fear conditioning test (Fig 2A). During the training day, mice were placed in a training context and received brief aversive stimuli (footshock, 2×, 0.5 mA, 2 s duration, 30 s interval; Clark et al , 2008; Ujjainwala et al , 2019). On the test day (24 h after the training), mice were re‐exposed to the training context and assessed for fear memory by measuring freezing behavior in the absence of footshock stimuli.…”

“…We then employed the Barnes maze to determine whether the loss of Nedd4‐2 impacts spatial reference memory (Fig 2B, left; Ujjainwala et al , 2019). The mice were first trained to escape a brightly lighted circular field by finding a dark escape hole.…”

“…We next examined the mice in a novel object recognition test for recognition memory (Fig 2C; Lueptow, 2017; Ujjainwala et al , 2019). During the test, mice were placed in a testing box containing two identical objects and allowed to explore those objects for 10 min.…”