Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

Abstract

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.

Calcium-dependent activator protein for secretion 2 (CAPS2) promotes BDNF secretion and is critical for the development of GABAergic interneuron network

“…Moreover, theta oscillation (35) and the hippocampal GABAergic system play a prominent role in certain forms of emotional processing, with special emphasis on anxiety-like behavior (23)(24)(25). The present study showed that CAPS2-KO mice exhibited not only decreased frequency of hippocampal theta oscillations but also increased anxiety-like behavior.…”

“…S6). Impaired hippocampal GABA neurotransmission and decreased BDNF levels are thought to affect hippocampus-related learning and anxiety-like behavior (23)(24)(25). Interestingly, CAPS2-KO mice displayed increased anxiety-like behavior (Table S1) but showed little impairment in learning and memory tests.…”

Canonical TGF-β Signaling Is Required for the Balance of Excitatory/Inhibitory Transmission within the Hippocampus and Prepulse Inhibition of Acoustic Startle

“…There is also evidence that TGF-␤ signaling contributes to neurodegeneration in Alzheimer's disease (Tesseur et al, 2006;Ueberham et al, 2006) and altered cognitive abilities (Loeys et al, 2005). In addition, it has been found that components of TGF-␤ signaling pathway are altered in the hippocampus in human psychiatric conditions such as schizophrenia and bipolar disorder (Benes et al, 2007), and manipulation of TGF-␤ signaling has been proposed as a possible treatment for anxiety and depression (Dow et al, 2005;Ageta et al, 2008;Zheng et al, 2009).…”

“…TGF-␤ signaling also regulates synaptic transmission and plasticity in multiple circuits in different organisms including glutamergic transmission at the Drosophila neural muscular junction (McCabe et al, 2004), cholinergic transmission between motoneurons and interneurons in the CNS of Drosophila (Baines, 2004), glutamergic transmission between sensory and motor neurons in Aplysia ganglia (Zhang et al, 1997), and modulation of hippocampal network in mammals (Fukushima et al, 2007;Sun et al, 2007;Zheng et al, 2009).…”

Possible Role of TGF – B Pathways in Schizophrenia / Moguća Uloga TTGF - B Signalnih Puteva U Shizofreniji

“…Signalling through the canonical pathway is involved in multiple aspects of neurodevelopment, adult neurogenesis and neuroprotection (reviewed in 33). There is evidence that TGF signalling contributes to neurodegeneration in Alzheimer's disease (34,35) and influences cognitive abilities and the level of cognitive decline between male and female schizophrenia patients (36,37); further, it is altered in the hippocampus in schizophrenia and bipolar disorder (38) and in anxiety and depression (39)(40)(41).…”