Enhanced Learning and Memory and Altered GABAergic Synaptic Transmission in Mice Lacking the α5 Subunit of the GABA<sub>A</sub>Receptor

Collinson, Neil; Kuenzi, Frederick M.; Jarolimek, Wolfgang; Maubach, Karen A.; Cothliff, Rosa; Sur, Cyrille; Smith, Alison J.; Otu, Franklin M.; Howell, Owain; Atack, John; McKernan, Ruth M.; Seabrook, Guy R.; Dawson, G. R.; Whiting, Paul J.; Rosahl, Thomas W.

doi:10.1523/jneurosci.22-13-05572.2002

Cited by 578 publications

(478 citation statements)

References 45 publications

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“…In fact, mutant mice lacking the a5 subunit of the GABA A receptor, which is important for tonic inhibition (see above), showed enhanced learning and memory. 47 The idea that activin, by reducing GABA tonus, would also improve cognitive performance is particularly intriguing in light of our previous study on the role of activin in excitatory neurotransmission. There, we reported that activin augments NMDA receptor currents and promotes hippocampal LTP.…”

Section: Discussionmentioning

confidence: 99%

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

Zheng

Adelsberger²,

et al. 2008

Mol Psychiatry

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Activin, a member of the transforming growth factor-b superfamily, affords neuroprotection in acute brain injury, but its physiological functions in normal adult brain are largely unknown. Using transgenic (tg) mice expressing a dominant-negative activin receptor mutant under the control of the CaMKIIa promoter in forebrain neurons, we identified activin as a key regulator of c-aminobutyric acid (GABA)ergic synapses and anxiety-like behavior. In the open field, wildtype (wt) and tg mice did not differ in spontaneous locomotion and exploration behavior. However, tg mice visited inner fields significantly more often than wt mice. In the light-dark exploration test, tg mice made more exits, spent significantly more time on a well-lit elevated bar and went farther away from the dark box as compared to wt mice. In addition, the anxiolytic effect of diazepam was abrogated in tg mice. Thus the disruption of activin receptor signaling produced a low-anxiety phenotype that failed to respond to benzodiazepines. In whole-cell recordings from hippocampal pyramidal cells, enhanced spontaneous GABA release, increased GABA tonus, reduced benzodiazepine sensitivity and augmented GABA B receptor function emerged as likely substrates of the low-anxiety phenotype. These data provide strong evidence that activin influences pre-and postsynaptic components of GABAergic synapses in a highly synergistic fashion. Given the crucial role of GABAergic neurotransmission in emotional states, anxiety and depression, dysfunctions of activin receptor signaling could be involved in affective disorders: and drugs affecting this pathway might show promise for psychopharmacological treatment.

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Section: Discussionmentioning

confidence: 99%

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

Zheng

Adelsberger²,

et al. 2008

Mol Psychiatry

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“…Evidently, all three newly synthesized BZ site ligands could have acted through the a 5 subtype-containing GABA A receptors, one of them (SH-053-R-CH3) as an essentially subtype-selective ligand. There exist data that support the possibility of substantial motor manifestations of a5-containing GABA A receptor modulation, besides the indirect consequences brought on by the effects on learning and memory processes, where pertinent (Collinson et al, 2002;Crestani et al, 2002). Somatic and preganglionic motoneurons in the spinal cord exhibit a moderate-to-strong staining for the a5 subunit (Bohlhalter et al, 1996), whereas the knock-in mice harboring the a5 subunit insensitive to diazepam are refractory to development of tolerance to the sedative effect of diazepam dosed subchronically, presumably due to a downregulation of a5 subunits in the dentate gyrus (van Rijnsoever et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Knock-in mice with the GABA A receptor a5 subunit rendered insensitive to diazepam were refractory to development of tolerance to the sedative effect of diazepam dosed subchronically (van Rijnsoever et al, 2004). These two sets of evidence indicate that the motor influence of a5-GABA A receptor modulation, if present, is not necessarily an indirect consequence of the established effects on learning and memory processes (Collinson et al, 2002;Crestani et al, 2002). Hence, any activity changes seen with ligands possessing a substantial agonistic efficacy for a5 subunit containing GABA A receptors may be, at least partly, mediated by such receptors.…”

Section: Introductionmentioning

confidence: 91%

Are GABAA Receptors Containing α5 Subunits Contributing to the Sedative Properties of Benzodiazepine Site Agonists?

Savić

Huang

Furtmüller

et al. 2007

Neuropsychopharmacol

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Classical benzodiazepines (BZs) exert anxiolytic, sedative, hypnotic, muscle relaxant, anticonvulsive, and amnesic effects through potentiation of neurotransmission at GABA A receptors containing a 1 , a 2 , a 3 or a 5 subunits. Genetic studies suggest that modulation at the a 1 subunit contributes to much of the adverse effects of BZs, most notably sedation, ataxia, and amnesia. Hence, BZ site ligands functionally inactive at GABA A receptors containing the a 1 subunit are considered to be promising leads for novel, anxioselective anxiolytics devoid of sedative properties. In pursuing this approach, we used two-electrode voltage clamp experiments in Xenopus oocytes expressing recombinant GABA A receptor subtypes to investigate functional selectivity of three newly synthesized BZ site ligands and also compared their in vivo behavioral profiles. The compounds were functionally selective for a 2 -, a 3 -, and a 5 -containing subtypes of GABA A receptors (SH-053-S-CH3 and SH-053-S-CH3-2 0 F) or essentially selective for a 5 subtypes (SH-053-R-CH3). Possible influences on behavioral measures were tested in the elevated plus maze, spontaneous locomotor activity, and rotarod test, which are considered primarily predictive of the anxiolytic, sedative, and ataxic influence of BZs, respectively. The results confirmed the substantially diminished ataxic potential of BZ site agonists devoid of a 1 subunit-mediated effects, with preserved anti-anxiety effects at 30 mg/kg of SH-053-S-CH3 and SH-053-S-CH3-2 0 F. However, all three ligands, dosed at 30 mg/kg, decreased spontaneous locomotor activity, suggesting that sedation may be partly dependent on activity mediated by a 5 -containing GABA A receptors. Hence, it could be of importance to avoid substantial agonist activity at a 5 receptors by candidate anxioselective anxiolytics, if clinical sedation is to be avoided.

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“…These receptors are known regulators of neurogenesis (50). RA is also known to induce differentiation of several neuronal progenitors toward a phenotype of GABAA receptor expression (51,52), and these receptors are essential for hippocampal-mediated cognitive function via regulation of synaptic transmission (53). A third mechanism may be proposed based on the influence of RA on hippocampal long-term potentiation and long-term depression.…”

Section: Discussionmentioning

confidence: 99%

13- cis -retinoic acid suppresses hippocampal cell division and hippocampal-dependent learning in mice

Crandall

Sakai

Zhang

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

197

170

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The active component of the acne drug Accutane is 13-cis-retinoic acid (RA), and it is highly teratogenic for the developing central nervous system. Very little is known, however, regarding the effect of this drug on the adult brain. Regions of the brain that may be susceptible to RA are those that continue to generate new neurons. In the adult mouse, neurogenesis is maintained in the hippocampus and subventricular zone. This report demonstrates that a clinical dose (1 mg͞kg͞day) of 13-cis-RA in mice significantly reduces cell proliferation in the hippocampus and the subventricular zone, suppresses hippocampal neurogenesis, and severely disrupts capacity to learn a spatial radial maze task. The results demonstrate that the regions of the adult brain where cell proliferation is ongoing are highly sensitive to disruption by a clinical dose of 13-cis-RA.A ccutane, the active component of which is 13-cis-retinoic acid (RA), is the primary treatment for chronic acne. RA induces differentiation and reduces proliferation of stem and progenitor cells, and 13-cis-RA helps control acne by inducing similar events in basal sebocytes (1). These same actions also lead to 13-cis-RA's side effects, and these are directed toward proliferating cells in the adult such as in the skin, gut, and bone (2). However, Accutane has also been reported to modify behavior, sometimes resulting in severe depression with suicidal ideation (2-4). It is surprising that 13-cis-RA might influence the adult brain, an organ in which there is not extensive proliferation. Certainly, this effect has been considered contentious (5), in large part because no mechanism has been described for such an etiology. Cell proliferation, however, is known to occur in restricted regions of the adult brain. New neurons are born and develop in the subgranular zone (SGZ) of the hippocampal formation as well as in the subventricular zone (SVZ) of the forebrain and in its extension via the rostral migratory stream to the olfactory bulb (6). If 13-cis-RA influences the brain, then these proliferating cells would be likely targets. We show, in a mouse model, that 13-cis-RA, at a dose of 1 mg͞kg͞day, reduces both the rate of hippocampal cell birth and the number of newborn neurons. Because the hippocampus is primarily associated with memory processing, and new neuronal birth has been suggested to be required for this task (7), it would also be predicted that 13-cis-RA would result in a decline in hippocampal-dependent memory. In this study, we demonstrate that, by using a radial arm maze test, there is a severe defect in the ability of 13-cis-RA-injected mice to perform this task, suggesting that long-term exposure to 13-cis-RA can disrupt hippocampaldependent behavior. MethodsBrdUrd Treatment. Mice were injected with BrdUrd in two types of experimental paradigms, the first to determine the influence of RA on the rate of cell proliferation in the hippocampus and the second as a cell marker to follow cell survival. To follow cell proliferation (Fig. 1A), RA was injected dail...

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Enhanced Learning and Memory and Altered GABAergic Synaptic Transmission in Mice Lacking the α5 Subunit of the GABA_AReceptor

Cited by 578 publications

References 45 publications

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

Are GABAA Receptors Containing α5 Subunits Contributing to the Sedative Properties of Benzodiazepine Site Agonists?

13- cis -retinoic acid suppresses hippocampal cell division and hippocampal-dependent learning in mice

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Enhanced Learning and Memory and Altered GABAergic Synaptic Transmission in Mice Lacking the α5 Subunit of the GABAAReceptor

Cited by 578 publications

References 45 publications

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

Are GABAA Receptors Containing α5 Subunits Contributing to the Sedative Properties of Benzodiazepine Site Agonists?

13- cis -retinoic acid suppresses hippocampal cell division and hippocampal-dependent learning in mice

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Enhanced Learning and Memory and Altered GABAergic Synaptic Transmission in Mice Lacking the α5 Subunit of the GABA_AReceptor