The physiological modulation by intracellular kinases of hippocampal γ-oscillation in vitro.

Hippocampal network oscillations at gamma frequency band (γ-oscillation, 20-80 Hz) are synchronized synaptic activities generated by the interactions between the excitatory and inhibitory interneurons and are associated with higher brain function such as learning and memory. Despite extensive studies about the modulation of intracellular kinases on synaptic transmission and plasticity, little is known about the effects of these kinases on γ-oscillations. In this study, we examined the effects of several critical intracellular kinases such as cyclic AMP-dependent protein kinase (PKA), protein kinase B (PKB)/Akt, protein kinase C (PKC), extracellular-regulated protein kinases (ERK) and AMP-activated protein kinase (AMPK), known to regulate synaptic transmission, on hippocampal γ-oscillations in vitro. We found that AMPK inhibitor but not PKA, PKC, or ERK inhibitor, strongly enhanced the power of γ-oscillation (γ-power) and that Akt inhibitor weakly increased γ-power. Western blot analysis confirmed that AMPK inhibitor reduced the expression of p-AMPK but not total AMPK. By using the slice whole cell voltage-clamp technique, we found that AMPK inhibitor increased the frequency but not amplitude of spontaneous inhibitory postsynaptic currents (sIPSC) and had no effect on either frequency or amplitude of spontaneous excitatory postsynaptic currents (sEPSC). Therefore, AMPK activation negatively modulates hippocampal γ-oscillation via modulation of the inhibitory neurons.

Levetiracetam induction of theta frequency oscillations in rodent hippocampus in vitro.

Levetiracetam (LEV) has been demonstrated to improve cognitive function. Hippocampal theta rhythm (4-12 Hz) is associated with a variety of cognitively related behaviors, such as exploration in both humans and animal models. We investigated the effects of LEV on the theta rhythm in the rat hippocampal CA3 in hippocampal slices in vitro. We found that LEV increased the theta power in a dose-dependent manner. The increase in theta power can be blocked by GABAA receptor (GABAAR) or NMDA receptor (NMDAR) antagonists but not by AMPA receptor antagonist, indicating the involvement of GABAAR and NMDAR in the induction of theta activity. Interestingly, LEV enhancement of theta power can be also blocked by taurine or GABA-A agonist THIP, indicating that LEV induction of theta may be related to the indirect boosting of GABA action via reduction of extrasynaptic GABAAR activation. Furthermore, the increased theta power can be partially reduced by the mACh receptor (mAChR) antagonist atropine but not by nACh receptor antagonists, suggesting that mAChR activation provides excitatory input into local network responsible for LEV-induced theta. Our study demonstrated that LEV induced a novel theta oscillation in vitro, which may have implications in the treatment of the neuronal disorders with impaired theta oscillation and cognitive function.

Alcohol use disorder disrupts BDNF maturation via the PAI-1 pathway which could be reversible with abstinence.

The plasminogen activator inhibitor-1 (PAI-1)→mature brain-derived neurotrophic factor (mBDNF) pathway plays a pivotal role in the conversion of probrain-BDNF (ProBDNF) to mBDNF, but its clinical relevance in patients with alcohol use disorder (AUD) remains unknown. Enzyme-linked immunosorbent assays were used to examine the relevant protein levels of components of the PAI-1→mBDNF pathway in plasma samples from three groups of subjects, and statistical analysis was performed using analysis of variance (ANOVA) and one-way repeated-measures ANOVA. Our findings revealed significant alterations induced by alcohol. (1) AUD was associated with significant decreases in tissue plasminogen activator (tPA), mBDNF, and tropomyosin receptor kinase B (TrkB); significant increases in PAI-1, ProBDNF, and P75 neurotrophin receptor (P75NTR); and inhibited conversion of ProBDNF to mBDNF. (2) Following abstinence, the levels of tPA, mBDNF, and TrkB in the AUD group significantly increased, whereas the levels of PAI-1, ProBDNF, and P75NTR significantly decreased, promoting the conversion of ProBDNF to mBDNF. These clinical outcomes collectively suggest that AUD inhibits the conversion of ProBDNF to mBDNF and that abstinence reverses this process. The PAI-1→mBDNF cleavage pathway is hypothesized to be associated with AUD and abstinence treatment.

The Cellular Mechanisms of Dopamine Modulation on the Neuronal Network Oscillations in the CA3 Area of Rat Hippocampal Slices.

Network oscillations at γ frequency band (30-80 Hz), generated by the interaction between inhibitory interneurons and excitatory neurons, have been proposed to be associated with higher brain functions such as learning and memory. Dopamine (DA), one of the major CNS transmitters, modulates hippocampal γ oscillations but the intracellular mechanisms involved remain elusive. In this study, we recorded kainate-induced γ oscillations in the CA3 area of rat hippocampal slices, and found that DA strongly enhanced γ power, which was largely blocked by dopamine receptor 1 (DR1) antagonist SCH23390, receptor tyrosine kinase (RTK) inhibitor UNC569 and ERK inhibitor U0126, partially blocked by D2/3R antagonist raclopride, PKA inhibitor H89 and PI3K inhibitor wortmannin, but not affected by AKT inhibitor TCBN or NMDAR antagonist D-AP5. Our results indicate that DA-mediated γ enhancement is involved in the activation of signaling pathway of DR1/2-RTK-ERK. Our data demonstrate a strong, rapid modulation of DA on hippocampal γ oscillations and provide a new insight into cellular mechanisms of DA-mediated γ oscillations.

The Modulation of Gamma Oscillations by Methamphetamine in Rat Hippocampal Slices.

Gamma frequency oscillations (γ, 30-100 Hz) have been suggested to underlie various cognitive and motor functions. The psychotomimetic drug methamphetamine (MA) enhances brain γ oscillations associated with changes in psychomotor state. Little is known about the cellular mechanisms of MA modulation on γ oscillations. We explored the effects of multiple intracellular kinases on MA modulation of γ induced by kainate in area CA3 of rat ventral hippocampal slices. We found that dopamine receptor type 1 and 2 (DR1 and DR2) antagonists, the serine/threonine kinase PKB/Akt inhibitor and N-methyl-D-aspartate receptor (NMDAR) antagonists prevented the enhancing effect of MA on γ oscillations, whereas none of them affected baseline γ strength. Protein kinase A, phosphoinositide 3-kinase and extracellular signal-related kinases inhibitors had no effect on MA. We propose that the DR1/DR2-Akt-NMDAR pathway plays a critical role for the MA enhancement of γ oscillations. Our study provides an new insight into the mechanisms of acute MA on MA-induced psychosis.