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1.
Figure 2

Figure 2. Mechanisms of AD action in immature neurons of the dentate gyrus involving GABAergic transmission. From: The GABAergic Deficit Hypothesis of Major Depressive Disorder.

A. GABAARs in immature neurons conduct an inward current (Cl ions moving out of the cell) due to the more positive Cl reversal potential in these cells. The ensuing membrane depolarization facilitates Ca2+ entry through V-gated ion channels such as the T-type and L-type voltage gated Ca2+ channels, and in more mature neurons also NMDARs. The cytoplasmic increase in Ca2+ results in an increased activity of protein kinases (CaMKII, PKC, PKA, others) that phosphorylate CREB on Ser133. Phosphorylated CREB translocates to the nucleus where it activates a number of target genes including that encoding BDNF. B. Increased production and release of BDNF acts on GABAergic terminals and promotes the release of GABA by TrkB/MAPK-mediated phosphorylation of synapsin and mobilization of GABA-containing vesicles, and by activation of P/Q-type voltage-gated Ca2+ channels that activate the neurotransmitter release machinery. C, Monoamine transmitters, which are presumed to be elevated in the hippocampus upon AD treatment, act on presynaptic β-adrenergic and 5-HTRs that activate voltage-gated Ca2+ channels on terminals and soma of GABAergic interneurons. D, Some effects of monoamine transmitters may be mediated by GPCRs on granule cells. However, the expression of these receptors on neural progenitors and immature granule cells has not been documented.

Bernhard Luscher, et al. Mol Psychiatry. ;16(4):383-406.
2.
Figure 1

Figure 1. HPA axis hyperactivation by frontocortical and hippocampal deficits in GABAergic inhibition. From: The GABAergic Deficit Hypothesis of Major Depressive Disorder.

The GABAergic deficit hypothesis of MDD presented here suggests that local GABAergic deficits in hippocampus and frontal cortex due to reduced GABA release, uncoordinated GABAAR subunit gene expression or anomalous signaling mechanisms that affect GABAAR accumulation at the plasma membrane lead to local hyperexcitability, which is relayed by projections (In the case of frontal cortex through the BNST 144) to the PVN of the hypothalamus. In the hippocampus such local GABAergic deficits may involve loss of parvalbumin positive interneurons 131, reduced GABAergic synaptic inhibition 130 and reduced maturation and survival of adult-born granule cells 108, which is sufficient to activate the HPA axis 135. Cortical deficits in GABAergic inhibition include reduced GABA levels in patients 61,62. In addition, GABAergic deficits may be induced by chronic stress, which down-regulates the expression and function of GABAARs in the frontal cortex 112. Hyperexcitability of the cortex and hippocampus is relayed by projections to the PVN. Local GABAergic inhibition of PVN neurons may be independently compromised by a stress-induced shift in the neural Cl reversal potential 147. The ensuing excessive release of CRH from the PVN results in increased release of ACTH from the anterior pituitary, which promotes the release of glucocorticoids, thereby closing a positive feedback loop that amplifies cortical and hippocampal GABAergic deficits. Adrenal neurosteroids normally potentiate GABA-mediated activation of GABAARs on dentate gyrus granule cells 168,381. Moreover THDOC upregulates the expression of α4βδ receptors in hippocampal granule cells 115. However, in CA1 pyramidal cells of the hippocampus the same neurosteroids facilitate GABA-induced desensitization of α4βδ receptors 153, which increases neural excitability 168.

Bernhard Luscher, et al. Mol Psychiatry. ;16(4):383-406.

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