Smad3 deficiency inhibits dentate gyrus LTP by enhancing GABA_A neurotransmission

Abstract

Transforming growth factor-b signaling through intracellular Smad3 has been implicated in Parkinson's disease (PD) and it fulfills an important role in the neurogenesis and synaptic plasticity that occurs in the adult dentate gyrus (DG). The longterm potentiation (LTP) induced in the DG by high-frequency stimulation of the medial perforant pathway is abolished in the DG of Smad3-deficient mice, but not in the CA1 hippocampal region. Here, we show that NMDA-and AMPA-type glutamate receptors do not participate in the inhibition of LTP associated with Smad3 deficiency. Moreover, there is no difference in the hippocampal GAD65 and GAD67 content, suggesting that GABA biosynthesis remains unaffected. Increased conductance and higher action potential firing thresholds were evident in intracellular recordings of granule cells from Smad3 deficient mice. Interestingly, phasic and tonic GABA A receptor (GABA A R)-mediated neurotransmission is enhanced in the DG of Smad3-deficient mice, and LTP induction can be rescued by inhibiting GABA A R with picrotoxin. Hence, Smad3 signaling in the DG appears to be necessary to induce LTP by regulating GABA A neurotransmission, suggesting a central role of this intracellular signaling pathway in the hippocampal brain plasticity related to learning and memory.

Long-Term Continuous Cervical Spinal Cord Stimulation Exerts Neuroprotective Effects in Experimental Parkinson’s Disease

“…Moreover, these findings parallel the upregulation of VEGF in the lesioned striatum of PD rats that received intermittent SCS (1 h/day for 7 consecutive days) (Shinko et al, 2014). That SCS modulates specific vasculature-associated growth factors suggests a crosstalk between electrical stimulation and growth factor secretion (Bagetta et al, 2011;Escamilla-Sevilla et al, 2011;Seifried et al, 2013;Maioli et al, 2015;Muñoz et al, 2016), which may mediate the observed increase in laminin-positive vascular area in the cerebral cortex of SCS-treated PD rats.…”

Therapeutics of Neurotransmitters in Alzheimer’s Disease

“…High doses of the AChEI, i.e., donepezil, were licensed in the USA for moderate-severe AD, and the association AChEI with memantine was proposed for AD at this stage. Molino et al [131] reviewed different clinical trials regarding effectiveness of memantine, donepezil, or the two drugs in combination to manage moderate-severe AD. The authors considered double-blind, placebo-controlled, randomized trials, employing memantine, donepezil independently or in conjunction with memantine and compared to placebo treatments in moderately severe AD.…”

“…These results indicated selective inhibition of astrocytic GABA synthesis or release and may be useful for improving memory in AD [130]. In Parkinson’s disease, Smad3 deficiency as noted in GABA (A) neurotransmission was observed to increase through the inhibition of dentate gyrus LTP [131]. Similarly, alteration of GABA neurotransmission is thought to produce hippocampal cognitive dysfunction in Down’s syndrome patients with AD.…”

Neural mechanisms underlying GABAergic regulation of adult hippocampal neurogenesis

“…A recent study by Muñoz et al showed a new mouse model of Parkinson’s disease that could also be rescued by targeting GABA A receptors. Smad3 deficient mice fail to induce LTP in the dentate gyrus due to enhanced GABA A receptor-mediated activity, in addition to decreased adult neurogenesis and dysregulated hippocampal function (Muñoz et al, 2016). Picrotoxin, a GABA A antagonist, rescued this phenotype.…”