Trace fear conditioning is enhanced in mice lacking the subunit of the GABAA receptor

Psychology Department, and The Brain Research Institute, UCLA, Los Angeles, California 90095, USA.
Learning &amp Memory (Impact Factor: 3.66). 05/2005; 12(3):327-33. DOI: 10.1101/lm.89705
Source: PubMed


The delta subunit of the GABA(A) receptor (GABA(A)R) is highly expressed in the dentate gyrus of the hippocampus. Genetic deletion of this subunit reduces synaptic and extrasynaptic inhibition and decreases sensitivity to neurosteroids. This paper examines the effect of these changes on hippocampus-dependent trace fear conditioning. Compared to controls, delta knockout mice exhibited enhanced acquisition of tone and context fear. Hippocampus-independent delay conditioning was normal in these animals. These results suggest that reduced inhibition in the dentate gyrus facilitates the acquisition of trace fear conditioning. However, the enhancement in trace conditioning was only observed in female knockout mice. The sex-specificity of this effect may be a result of neuroactive steroids. These compounds vary during the estrus cycle, can increase GABAergic inhibition, and have been shown to impair hippocampus-dependent learning. We propose that activation of GABA(A)Rs by neuroactive steroids inhibits learning processes in the hippocampus. Knockouts are immune to this effect because of the reduced neurosteroid sensitivity that accompanies deletion of the delta subunit. Relationships between neurosteroids, hippocampal excitability, and memory are discussed.

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Article: Trace fear conditioning is enhanced in mice lacking the subunit of the GABAA receptor

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    • "First, enhanced δGABAA receptor activity constrains neuronal firing (Bonin et al., 2011), reduces network excitability (Maguire et al., 2009) and attenuates synaptic plasticity in the CA1 region of the hippocampus (Shen et al., 2010). Second, one of the primary molecular targets of THIP, the α4βδ GABAA receptor (Brown et al., 2002), constrains fear-associated memory (Wiltgen et al., 2005) as evidenced by studies of transgenic mice that lack either the δ subunit gene (Wiltgen et al., 2005) or the α4 subunit gene (Moore et al., 2010; Cushman et al., 2011). Interestingly, human studies have shown that THIP does not alter memory performance measured 12–24 h after drug treatment (Mathias et al., 2005; Boyle et al., 2009; Leufkens et al., 2009). "
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    ABSTRACT: Extrasynaptic γ-aminobutyric acid type A (GABAA) receptors that contain the δ subunit (δGABAA receptors) are expressed in several brain regions including the dentate gyrus (DG) and CA1 subfields of the hippocampus. Drugs that increase δGABAA receptor activity have been proposed as treatments for a variety of disorders including insomnia, epilepsy and chronic pain. Also, long-term pretreatment with the δGABAA receptor-preferring agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) enhances discrimination memory and increases neurogenesis in the DG. Despite the potential therapeutic benefits of such treatments, the effects of acutely increasing δGABAA receptor activity on memory behaviors remain unknown. Here, we studied the effects of THIP (4 mg/kg, i.p.) on memory performance in wild-type (WT) and δGABAA receptor null mutant (Gabrd(-/-)) mice. Additionally, the effects of THIP on long-term potentiation (LTP), a molecular correlate of memory, were studied within the DG and CA1 subfields of the hippocampus using electrophysiological recordings of field potentials in hippocampal slices. The results showed that THIP impaired performance in the Morris water maze, contextual fear conditioning and object recognition tasks in WT mice but not Gabrd(-/-) mice. Furthermore, THIP inhibited LTP in hippocampal slices from WT but not Gabrd(-/-) mice, an effect that was blocked by GABAA receptor antagonist bicuculline. Thus, acutely increasing δGABAA receptor activity impairs memory behaviors and inhibits synaptic plasticity. These results have important implications for the development of therapies aimed at increasing δGABAA receptor activity.
    Frontiers in Neural Circuits 09/2013; 7:146. DOI:10.3389/fncir.2013.00146 · 3.60 Impact Factor
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    • "Although the dentate gyrus circuitry plays a role in the formation of these memories, the specific effect is complex and the outcome of α4βδ knock-out depends on the task examined. Both α4 and δ knock-out enhance trace and conditional fear conditioning (Wiltgen et al., 2005; Moore et al., 2010). However, δ knock-out impairs recognition memory and contextual discrimination memory, suggesting that these receptors facilitate these types of plasticity (Whissell et al., 2013). "
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    ABSTRACT: The onset of puberty is associated with alterations in mood as well as changes in cognitive function, which can be more pronounced in females. Puberty onset in female mice is associated with increased expression of α4βδ γ-amino-butyric acid-A (GABAA) receptors (GABARs) in CA1 hippocampus. These receptors, which normally have low expression in this central nervous system (CNS) site, emerge along the apical dendrites as well as on the dendritic spines of pyramidal neurons, adjacent to excitatory synapses where they underlie a tonic inhibition that shunts excitatory current and impairs activation of N-methyl-D-aspartate (NMDA) receptors, the trigger for synaptic plasticity. As would be expected, α4βδ expression at puberty also prevents long-term potentiation (LTP), an in vitro model of learning which is a function of network activity, induced by theta burst stimulation of the Schaffer collaterals to the CA1 hippocampus. The expression of these receptors also impairs spatial learning in a hippocampal-dependent task. These impairments are not seen in δ knock-out (-/-) mice, implicating α4βδ GABARs. α4βδ GABARs are also a sensitive target for steroids such as THP ([allo]pregnanolone or 3α-OH-5α[β]-pregnan-20-one), which are dependent upon the polarity of GABAergic current. It is well-known that THP can increase depolarizing current gated by α4βδ GABARs, but more recent data suggest that THP can reduce hyperpolarizing current by accelerating receptor desensitization. At puberty, THP reduces the hyperpolarizing GABAergic current, which removes the shunting inhibition that impairs synaptic plasticity and learning at this time. However, THP, a stress steroid, also increases anxiety, via its action at α4βδ GABARs because it is not seen in δ(-/-) mice. These findings will be discussed as well as their relevance to changes in mood and cognition at puberty, which can be a critical period for certain types of learning and when anxiety disorders and mood swings can emerge.
    Frontiers in Neural Circuits 09/2013; 7:135. DOI:10.3389/fncir.2013.00135 · 3.60 Impact Factor
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    • "However, these results are inconsistent. Although some studies have reported no sex differences [19,20], others have reported that in humans and rodents, males tend to exhibit higher conditioning responses relative to females [21,22]. As for fear extinction, we recently reported data showing that estradiol significantly enhances extinction recall in female rats and in women [23]. "
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    ABSTRACT: The amygdala, hippocampus, medial prefrontal cortex (mPFC) and brain-stem subregions are implicated in fear conditioning and extinction, and are brain regions known to be sexually dimorphic. We used functional magnetic resonance imaging (fMRI) to investigate sex differences in brain activity in these regions during fear conditioning and extinction. Subjects were 12 healthy men comparable to 12 healthy women who underwent a 2-day experiment in a 3 T MR scanner. Fear conditioning and extinction learning occurred on day 1 and extinction recall occurred on day 2. The conditioned stimuli were visual cues and the unconditioned stimulus was a mild electric shock. Skin conductance responses (SCR) were recorded throughout the experiment as an index of the conditioned response. fMRI data (blood-oxygen-level-dependent [BOLD] signal changes) were analyzed using SPM8. Findings showed no significant sex differences in SCR during any experimental phases. However, during fear conditioning, there were significantly greater BOLD-signal changes in the right amygdala, right rostral anterior cingulate (rACC) and dorsal anterior cingulate cortex (dACC) in women compared with men. In contrast, men showed significantly greater signal changes in bilateral rACC during extinction recall. These results indicate sex differences in brain activation within the fear circuitry of healthy subjects despite similar peripheral autonomic responses. Furthermore, we found that regions where sex differences were previously reported in response to stress, also exhibited sex differences during fear conditioning and extinction.
    Biology of Mood and Anxiety Disorders 04/2012; 2(1):7. DOI:10.1186/2045-5380-2-7
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