Person:

Bolshakov, Vadim

Changes in synaptic strength are believed to underlie learning and memory. We explore the idea that norepinephrine is an essential modulator of memory through its ability to regulate synaptic mechanisms. Emotional arousal leads to activation of the locus coeruleus with the subsequent release of norepineprine in the brain, resulting in the enhancement of memory. Norepinephrine activates both pre- and post-synaptic adrenergic receptors at central synapses with different functional outcomes, depending on the expression pattern of these receptors in specific neural circuitries underlying distinct behavioral processes. We review the evidence for noradrenergic modulation of synaptic plasticity with consideration of how this may contribute to the mechanisms of learning and memory.

Kainate receptor (KAR) subunits are believed to be involved in abnormal GABAergic neurotransmission in the hippocampus (HIPP) in schizophrenia (SZ) and bipolar disorder. Postmortem studies have shown changes in the expression of the GluR5/6 subunits of KARs in the stratum oriens (SO) of sectors CA2/3, where the basolateral amygdala (BLA) sends a robust projection. Previous work using a rat model of SZ demonstrated that BLA activation leads to electrophysiological changes in fast-spiking interneurons in SO of CA2/3. The present study explores KAR modulation of interneurons in CA2/3 in response to BLA activation. Intrinsic firing properties of these interneurons through KAR-mediated activity were measured with patch-clamp recordings from rats that received 15 days of picrotoxin infusion into the BLA. Chronic BLA activation induced changes in the firing properties of CA2/3 interneurons associated with modifications in the function of KARs. Specifically, the responsiveness of these interneurons to activation of KARs was diminished in picrotoxin-treated rats, while the after-hyperpolarization (AHP) amplitude was increased. In addition, we tested blockers of KAR subunits which have been shown to have altered gene expression in SO sector CA2/3 of SZ subjects. The GluR5 antagonist UBP296 further decreased AP frequency and increased AHP amplitude in picrotoxin-treated rats. Application of the GluR6/7 antagonist NS102 suggested that activation of GluR6/7 KARs may be required to maintain the high firing rates in SO interneurons in the presence of KA. Moreover, the GluR6/7 KAR-mediated signaling may be suppressed in PICRO-treated rats. Our findings indicate that glutamatergic activity from the BLA may modulate the firing properties of CA2/3 interneurons through GluR5 and GluR6/7 KARs. These receptors are expressed in GABAergic interneurons and play a key role in the synchronization of gamma oscillations. Modulation of interneuronal activity through KARs in response to amygdala activation may lead to abnormal oscillatory rhythms reported in SZ subjects.

Mechanisms of NMDA receptor-dependent synaptic plasticity contribute to the acquisition and retention of conditioned fear memory. However, synaptic rules which may determine the extent of NMDA receptor activation in the amygdala, a key structure implicated in fear learning, remain unknown. Here we show that the identity of the NMDAR glycine site agonist at synapses in the lateral nucleus of the amygdala may depend on the level of synaptic activation. Tonic activation of NMDARs at synapses in the amygdala under low-activity conditions is supported by ambient D-serine, whereas glycine may be released from astrocytes in response to afferent impulses. The release of glycine may decode the increases in afferent activity levels into enhanced NMDAR-mediated synaptic events, serving an essential function in the induction of NMDAR-dependent long-term potentiation in fear conditioning pathways.

Understanding basic neuronal mechanisms hold the hope for future treatment of brain disease. The 1st international conference on synapse, memory, drug addiction and pain was held in beautiful downtown Toronto, Canada on August 21–23, 2006. Unlike other traditional conferences, this new meeting focused on three major aims: (1) to promote new and cutting edge research in neuroscience; (2) to encourage international information exchange and scientific collaborations; and (3) to provide a platform for active scientists to discuss new findings. Up to 64 investigators presented their recent discoveries, from basic synaptic mechanisms to genes related to human brain disease. This meeting was in part sponsored by Molecular Pain, together with University of Toronto (Faculty of Medicine, Department of Physiology as well as Center for the Study of Pain). Our goal for this meeting is to promote future active scientific collaborations and improve human health through fundamental basic neuroscience researches. The second international meeting on Neurons and Brain Disease will be held in Toronto (August 29–31, 2007).

Background: Presenilins play a major role in the pathogenesis of Alzheimer’s disease, in which the hippocampus is particularly vulnerable. Previous studies of Presenilin function in the synapse, however, focused exclusively on the hippocampal Schaffer collateral (SC) pathway. Whether Presenilins play similar or distinct roles in other hippocampal synapses is unknown. Methods: To investigate the role of Presenilins at mossy fiber (MF) synapses we performed field and whole-cell electrophysiological recordings and Ca2+ imaging using acute hippocampal slices of postnatal forebrain-restricted Presenilin conditional double knockout (PS cDKO) and control mice at 2 months of age. We also performed quantitative electron microscopy (EM) analysis to determine whether mitochondrial content is affected at presynaptic MF boutons of PS cDKO mice. We further conducted behavioral analysis to assess spatial learning and memory of PS cDKO and control mice at 2 months in the Morris water maze. Results: We found that long-term potentiation and short-term plasticity, such as paired-pulse and frequency facilitation, are impaired at MF synapses of PS cDKO mice. Moreover, post-tetanic potentiation (PTP), another form of short-term plasticity, is also impaired at MF synapses of PS cDKO mice. Furthermore, blockade of mitochondrial Ca2+ efflux mimics and occludes the PTP deficits at MF synapses of PS cDKO mice, suggesting that mitochondrial Ca2+ homeostasis is impaired in the absence of PS. Quantitative EM analysis showed normal number and area of mitochondria at presynaptic MF boutons of PS cDKO mice, indicating unchanged mitochondrial content. Ca2+ imaging of dentate gyrus granule neurons further revealed that cytosolic Ca2+ increases induced by tetanic stimulation are reduced in PS cDKO granule neurons in acute hippocampal slices, and that inhibition of mitochondrial Ca2+ release during high frequency stimulation mimics and occludes the Ca2+ defects observed in PS cDKO neurons. Consistent with synaptic plasticity impairment observed at MF and SC synapses in acute PS cDKO hippocampal slices, PS cDKO mice exhibit profound spatial learning and memory deficits in the Morris water maze. Conclusions: Our findings demonstrate the importance of PS in the regulation of synaptic plasticity and mitochondrial Ca2+ homeostasis in the hippocampal MF pathway.

Recent findings indicate a high level of specialization at the level of microcircuits and cell populations within brain structures with regards to the control of fear and anxiety. The hippocampus, however, has been treated as a unitary structure in anxiety and fear research despite mounting evidence that different hippocampal subregions have specialized roles in other cognitive domains. Using novel cell-type- and region-specific conditional knockouts of the GABAA receptor α2 subunit, we demonstrate that inhibition of the principal neurons of the dentate gyrus and CA3 via α2-containing GABAA receptors (α2GABAARs) is required to suppress anxiety, while the inhibition of CA1 pyramidal neurons is required to suppress fear responses. We further show that the diazepam-modulation of hippocampal theta activity shows certain parallels with our behavioral findings, suggesting a possible mechanism for the observed behavioral effects. Thus, our findings demonstrate a double dissociation in the regulation of anxiety versus fear by hippocampal microcircuitry. DOI: http://dx.doi.org/10.7554/eLife.14120.001