Postsynaptic burst reactivation of hippocampal neurons enables associative plasticity of temporally discontiguous inputs.

A fundamental unresolved problem in neuroscience is how the brain associates in memory events that are separated in time. Here, we propose that reactivation-induced synaptic plasticity can solve this problem. Previously, we reported that the reinforcement signal dopamine converts hippocampal spike timing-dependent depression into potentiation during continued synaptic activity (Brzosko et al., 2015). Here, we report that postsynaptic bursts in the presence of dopamine produce input-specific LTP in mouse hippocampal synapses 10 min after they were primed with coincident pre- and post-synaptic activity (post-before-pre pairing; Δt = -20 ms). This priming activity induces synaptic depression and sets an NMDA receptor-dependent silent eligibility trace which, through the cAMP-PKA cascade, is rapidly converted into protein synthesis-dependent synaptic potentiation, mediated by a signaling pathway distinct from that of conventional LTP. This synaptic learning rule was incorporated into a computational model, and we found that it adds specificity to reinforcement learning by controlling memory allocation and enabling both 'instructive' and 'supervised' reinforcement learning. We predicted that this mechanism would make reactivated neurons activate more strongly and carry more spatial information than non-reactivated cells, which was confirmed in freely moving mice performing a reward-based navigation task.

Modulation of hippocampal plasticity in learning and memory.

Synaptic plasticity plays a central role in the study of neural mechanisms of learning and memory. Plasticity rules are not invariant over time but are under neuromodulatory control, enabling behavioral states to influence memory formation. Neuromodulation controls synaptic plasticity at network level by directing information flow, at circuit level through changes in excitation/inhibition balance, and at synaptic level through modulation of intracellular signaling cascades. Although most research has focused on modulation of principal neurons, recent progress has uncovered important roles for interneurons in not only routing information, but also setting conditions for synaptic plasticity. Moreover, astrocytes have been shown to both gate and mediate plasticity. These additional mechanisms must be considered for a comprehensive mechanistic understanding of learning and memory.

Thalamus mediates neocortical Down state transition via GABAB-receptor-targeting interneurons.

Slow-wave sleep is characterized by near-synchronous alternation of active Up states and quiescent Down states in the neocortex. Although the cortex itself can maintain these oscillations, the full expression of Up-Down states requires intact thalamocortical circuits. Sensory thalamic input can drive the cortex into an Up state. Here we show that midline thalamic neurons terminate Up states synchronously across cortical areas. Combining local field potential, single-unit, and patch-clamp recordings in conjunction with optogenetic stimulation and silencing in mice in vivo, we report that thalamic input mediates Down transition via activation of layer 1 neurogliaform inhibitory neurons acting on GABAB receptors. These results strengthen the evidence that thalamocortical interactions are essential for the full expression of slow-wave sleep, show that Down transition is an active process mediated by cortical GABAB receptors, and demonstrate that thalamus synchronizes Down transitions across cortical areas during natural slow-wave sleep.

Increased basal antioxidant levels in RCAN1 - deficient mice lowers oxidative injury after acute paraquat insult.

RCAN1 is an inhibitor of the phosphatase calcineurin, which is involved in the regulation of oxidative stress and apoptosis, among other important cell processes. Here we have used RCAN1 deficient mice (RCAN1-/-) to elucidate its role after an acute oxidative insult such as paraquat injection. We have observed that RCAN1-/- mice show less oxidative damage than wildtype (WT) mice after treatment. Under basal conditions, RCAN1-/- animals express more calcineurin, heme oxygenase-1, Nrf2, and catalase compared to WT mice (controls). This may explain the less severe effect of paraquat treatment on RCAN1-/- mice compared to WT. We showed that oxidative stress is involved in the early stages of apoptosis, thus we determined the apoptotic effector BAD and found that decreases in RCAN1-/- mice after treatment with paraquat compared with WT in similar experimental conditions. Our results suggest that RCAN1 may be involved in the balance between oxidant and antioxidant species production in vivo.

Oral Monosodium Glutamate Administration Causes Early Onset of Alzheimer's Disease-Like Pathophysiology in APP/PS1 Mice.

Glutamate excitotoxicity has long been related to Alzheimer's disease (AD) pathophysiology, and it has been shown to affect the major AD-related hallmarks, amyloid-ß peptide (Aß) accumulation and tau phosphorylation (p-tau). We investigated whether oral administration of monosodium glutamate (MSG) has effects in a murine model of AD, the double transgenic mice APP/PS1. We found that AD pathogenic factors appear earlier in APP/PS1 when supplemented with MSG, while wildtype mice were essentially not affected. Aß and p-tau levels were increased in the hippocampus in young APP/PS1 animals upon MSG administration. This was correlated with increased Cdk5-p25 levels. Furthermore, in these mice, we observed a decrease in the AMPA receptor subunit GluA1 and they had impaired long-term potentiation. The Hebb-Williams Maze revealed that they had memory deficits. We show here for the first time that oral MSG supplementation can accelerate AD-like pathophysiology in a mouse model of AD.

Partial restoration of physiological UP-state activity by GABA pathway modulation in an acute brain slice model of epilepsy.

In addition to reducing seizures, anti-epileptic treatments should preserve physiological network activity. Here, we used a thalamocortical slice preparation displaying physiological slow oscillations to investigate the effects of anticonvulsant drugs on physiological activity and epileptiform activity in two pharmacological epilepsy models. Thus, we compared the effects of GABA pharmacology on spontaneous physiological and pathological events in slices of the mouse barrel cortex. We show that both reducing inhibition using GABAAR blockers and enhancing excitation by lowering Mg2+ concentration allow for the transition from physiological slow oscillations to epileptiform activity. Our results indicate that GABABR antagonists have pro-convulsive properties by increasing event duration in the low inhibition model and event frequency in the high excitation model. Moreover, we show that GABABR agonists and GABA uptake blockers, known for their anticonvulsant properties, act primarily on epileptiform burst frequency and allow for a partial restoration of physiological events. As a proof of principle, these results indicate that a slice model with spontaneous network events may be a useful pipeline to investigate the effects of anti-epileptic drugs on both epileptiform and physiological network activity.

New Functions of APC/C Ubiquitin Ligase in the Nervous System and Its Role in Alzheimer's Disease.

The E3 ubiquitin ligase Anaphase Promoting Complex/Cyclosome (APC/C) regulates important processes in cells, such as the cell cycle, by targeting a set of substrates for degradation. In the last decade, APC/C has been related to several major functions in the nervous system, including axon guidance, synaptic plasticity, neurogenesis, and neuronal survival. Interestingly, some of the identified APC/C substrates have been related to neurodegenerative diseases. There is an accumulation of some degradation targets of APC/C in Alzheimer's disease (AD) brains, which suggests a dysregulation of the protein complex in the disorder. Moreover, recently evidence has been provided for an inactivation of APC/C in AD. It has been shown that oligomers of the AD-related peptide, Aß, induce degradation of the APC/C activator subunit cdh1, in vitro in neurons in culture and in vivo in the mouse hippocampus. Furthermore, in the AD mouse model APP/PS1, lower cdh1 levels were observed in pyramidal neurons in CA1 when compared to age-matched wildtype mice. In this review, we provide a complete list of APC/C substrates that are involved in the nervous system and we discuss their functions. We also summarize recent studies that show neurobiological effects in cdh1 knockout mouse models. Finally, we discuss the role of APC/C in the pathophysiology of AD.

APC/Cdh E3 ubiquitin ligase in the pathophysiology of Alzheimer׳s disease.

The anaphase-promoting complex APC/C is a E3 ligase. It is regulates important functions in neural cells. Its inactivation and accumulation of its substrates has been related with neurodegenerative diseases. Glutaminase is an important target of APC/C-Cdh1 in primary neurons. It catalyzes the conversion of glutamine into glutamate. When cdh1 decreases due to incubation with Aß, glutaminase concentration increases as does cyclin B1, a known target of the ubiquitin ligase that is involved in the pathophysiology of Alzheimer's disease (AD). The same treatment causes a high increase of glutamate levels in the supernatant of neurons in culture, which subsequently leads to an increase of Ca(2) inside the cells. The increase of glutamate due to the Aß treatment can be partially reversed by a glutaminase inhibitor. This result suggests that the APC/C-Cdh1 signaling way is involved in the glutamate increase after the treatment with Aß. Moreover, high levels of glutamate have been observed to further decrease cdh1 levels what also leads to an accumulation of gls. These results lead us to propose that neurons might enter into a positive feedback loop of glutamate production due to a lack of APC/C-Cdh1 signaling. This signaling pathway reveals a new mechanism to cause excitotoxicity in neurons, which could be relevant in AD.