Synergistic Activation of Dopamine D1 and TrkB Receptors Mediate Gain Control of Synaptic Plasticity in the Basolateral Amygdala

Fear memory formation is thought to require dopamine, brain-derived neurotrophic factor (BDNF) and zinc release in the basolateral amygdala (BLA), as well as the induction of long term potentiation (LTP) in BLA principal neurons. However, no study to date has shown any relationship between these processes in the BLA. Here, we have used in vitro whole-cell patch clamp recording from BLA principal neurons to investigate how dopamine, BDNF, and zinc release may interact to modulate the LTP induction in the BLA. LTP was induced by either theta burst stimulation (TBS) protocol or spaced 5 times high frequency stimulation (5xHFS). Significantly, both TBS and 5xHFS induced LTP was fully blocked by the dopamine D1 receptor antagonist, SCH23390. LTP induction was also blocked by the BDNF scavenger, TrkB-FC, the zinc chelator, DETC, as well as by an inhibitor of matrix metalloproteinases (MMPs), gallardin. Conversely, prior application of the dopamine reuptake inhibitor, GBR12783, or the D1 receptor agonist, SKF39393, induced robust and stable LTP in response to a sub-threshold HFS protocol (2xHFS), which does not normally induce LTP. Similarly, prior activation of TrkB receptors with either a TrkB receptor agonist, or BDNF, also reduced the threshold for LTP-induction, an effect that was blocked by the MEK inhibitor, but not by zinc chelation. Intriguingly, the TrkB receptor agonist-induced reduction of LTP threshold was fully blocked by prior application of SCH23390, and the reduction of LTP threshold induced by GBR12783 was blocked by prior application of TrkB-FC. Together, our results suggest a cellular mechanism whereby the threshold for LTP induction in BLA principal neurons is critically dependent on the level of dopamine in the extracellular milieu and the synergistic activation of postsynaptic D1 and TrkB receptors. Moreover, activation of TrkB receptors appears to be dependent on concurrent release of zinc and activation of MMPs

Insulin-like Growth Factor-1 Prevents Hypoxia/Reoxygenation-Induced White Matter Injury in Sickle Cell Mice

Occlusion of cerebral blood vessels causes acute cerebral hypoxia—an important trigger of ischemic white matter injury and stroke in sickle cell disease (SCD). While chronic hypoxia triggers compensatory neuroprotection via insulin-like growth factor-1 (IGF-1) and hypoxia inducible factor-1α (HIF-1α), severe bouts of acute hypoxia and subsequent restoration of blood flow (hypoxia/reoxygenation, H/R) overwhelm compensatory mechanisms and cause neuroaxonal damage–identified as white matter lesions–in the brain. The neuroprotective role of IGF-1 in the pathogenesis of white matter injury in SCD has not been investigated; however, it is known that systemic IGF-1 is reduced in individuals with SCD. We hypothesized that IGF-1 supplementation may prevent H/R-induced white matter injury in SCD. Transgenic sickle mice homozygous for human hemoglobin S and exposed to H/R developed white matter injury identified by elevated expression of non-phosphorylated neurofilament H (SMI32) with a concomitant decrease in myelin basic protein (MBP) resulting in an increased SMI32/MBP ratio. H/R-challenge also lowered plasma and brain IGF-1 expression. Human recombinant IGF-1 prophylaxis significantly induced HIF-1α and averted H/R-induced white matter injury in the sickle mice compared to vehicle-treated mice. The expression of the IGF-1 binding proteins IGFBP-1 and IGFBP-3 was elevated in the IGF-1-treated brain tissue indicating their potential role in mediating neuroprotective HIF-1α signaling. This study provides proof-of-concept for IGF-1-mediated neuroprotection in SCD

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1279-1284Effect of chronic treatment of standardized aqueous extract of Moriga oleifera (MO) root (100,200,300,350,400,450mg/kg; po) on penicillin (PCN) induced convulsion,locomotor behaviour,brain ,serotonin(5-HT), dopamine (DA) and morepinephrine (NE) level was studied in Holtzman strain adult albino rats. The result revealed that pretreatment with MO inhibited PCN -induced, seizure and markedly reduced locomotor activity. Chronic treatment with MO significantly increased the 5-HT and decreased the DA level in cerebral cortex (CC),mid brain (MB), caudate nucleaus (CN) and cerebellum (C B), NE level was, signifi cantly decreased in CC but no appreciable change was observed in MB, CB and CN. Thus , the central inhibitory effect of MO is discussed in the light of the disturbed balance between 5-HT, DA and NE

<span style="font-size:12.0pt;line-height: 115%;font-family:"Times New Roman";mso-fareast-font-family:"Times New Roman"; mso-ansi-language:EN-IN;mso-fareast-language:EN-IN;mso-bidi-language:HI" lang="EN-IN">Role of 5-hydroxytryptamine in <i>Moringa</i> <i>oleifera</i> induced potentiation of pentobarbitone hypnosis in albino rats</span>

632-635<span style="font-size:12.0pt;line-height: 115%;font-family:" times="" new="" roman";mso-fareast-font-family:"times="" roman";="" mso-ansi-language:en-in;mso-fareast-language:en-in;mso-bidi-language:hi"="" lang="EN-IN">The role of 5-hydroxytryptamine (5-HT) in pentobarbitone (PB ) sleeping time, gross behaviour, electrical activity of the brain and serum 5-HT level was studied in Holtzman strain adult albino rats following treatment with M. oleifera (MO). MO (350mg/kg) caused inhibition of awareness, touch response, motor activity, righting reflex, and grip strength. It significantly increased the PB sleeping time, serum 5-HT level (P<0.001) and α-wave activity. These observations indicate that the aqueous extract of MO potentiated PB induced sleeping time and increased the α-wave activity through 5-HT.</span

Facilitation of LTP by GBR12783 and SKF38393 are dependent on activation of the cAMP - PKA signaling cascade.

<p><b>A</b>) Intracellular application of the PKA inhibitor, KT5720 (100 nM), blocked the GBR12783 facilitated LTP (n = 6) <b>B</b>) Application of KT5720 also fully blocked 5xHFS induced LTP in the presence of SKF38393 (n = 5) <b>C</b>) Bar chart showing the group data for drug effects 30 minutes post stimulation. *** P<0.001, Error bars indicate S.E.M.</p

Activation of the BDNF and TrkB pathway is critical for the induction of LTP in BLA principal neurons.

<p><b>A</b>) Bath application of of the non-selective receptor tyrosine kinase inhibitor, genistein (100 µM), before 5xHFS (arrow) blocked the induction of LTP in BLA principal neurons (n = 5, red squares). <b>B</b>) Bath application of the BDNF scavenger molecule, TrkB/Fc (1 µg/ml, n = 6), for 30 min before 5xHFS prevented the induction of LTP in BLA. <b>C</b>) Bar chart summarizing the group effects of modulating the BDNF and TrkB cascade on the induction of LTP. Intracellular application of MEK inhibitor, U0126 (10 µM, n = 5, hooped bar), for 30 min before recording abolished the induction of LTP. Similarly, bath application of the MMP inhibitor, GM6001 (Gallardin, 10 µM, n = 4, diagonal hashed bar), or the copper-zinc chelator (DETC, 20 µM, n = 5, stippled bar) significantly attenuated LTP in BLA principal neurons. ** P<0.01, * P<0.05. Error bars indicate SEM.</p

Stimulus dependent induction of LTP in BLA principal neurons.

<p><b>A</b>) A schematic illustrating the position of the stimulation (S_cortical and S_thalamic) and recording (R) electrodes. EC, external capsule. <b>B</b>) Stimulation of the EC elicits long term synaptic plasticity in BLA afferents following TBS (n = 6, blue diamonds) and 5×100 Hz (n = 5, red squares), but not 2×100 Hz (n = 8, green triangles). <b>C</b>) Raw data show the effects of different stimulation protocols on the PPR of EPSCs. EPSC amplitude was measured using paired stimuli pulses separated by 50 ms, before, immediately after, and 10 min and 30 min post stimulation. <b>D</b>) A bar chart showing the group data for the effects of stimulation protocol on PPR. Note the large decrease (P <0.05) immediately post-stim, indicating the presynaptic component of post-tetanic-potentiation. * P<0.05. Error bars indicate S.E.M.</p

D1 receptor-dependent reduction of the threshold of LTP induction requires calcium influx, and induction of the cAMP-PKA and MEK-MAPK signaling cascades.

<p><b>A</b>) Inclusion of the calcium chelator, BAPTA (10 mM) in the patch pipette (n = 5) abolished the GBR12783 mediated LTP induction by 2xHFS. <b>B</b>) Inclusion of the PKA inhibitor, KT5720 (100 nM) (n = 5) also blocked the GBR12783 mediated LTP induction by 2xHFS. <b>C</b>) Bar chart summarizing the group effects of GBR12783 on LTP induction using 2xHFS. As illustrated, pretreatment with SCH23390 (black bar), BAPTA (hooped bar), KT5720 (diagonal bar), and U0126 (hatched bar) all fully blocked the GBR12783-facilitated LTP (n = 5 in each case). ** P<0.01. Error bars indicate SEM.</p

D1 receptor activation acts to reduce the threshold for LTP induction in BLA principal neurons.

<p><b>A</b>) Application of the dopamine reuptake inhibitor GBR12783 (10 µM, n = 5), or <b>B</b>) the D1 receptor agonist SKF38393 (50 µM, n = 5) induced a robust and stable LTP in BLA principal neurons following 2xHFS. <b>C</b>) Raw data showing the effects of GBR12783 and SKF38393 on the PPR in BLA principal neurons. <b>D</b>) A bar chart illustrating the group effects of drug application on the PPR of EPSCs before, immediately after, and at 10 min and 30 min post 2xHFS. ** P<0.01. Error bars indicate S.E.M.</p