Rescue of synaptic and cognitive functions in polysialic acid-deficient mice and dementia models by short polysialic acid fragments.

Dysregulated cortical expression of the neural cell adhesion molecule (NCAM) and deficits of its associated polysialic acid (polySia) have been found in Alzheimer's disease and schizophrenia. However, the functional role of polySia in cortical synaptic plasticity remains poorly understood. Here, we show that acute enzymatic removal of polySia in medial prefrontal cortex (mPFC) slices leads to increased transmission mediated by the GluN1/GluN2B subtype of N-methyl-d-aspartate receptors (NMDARs), increased NMDAR-mediated extrasynaptic tonic currents, and impaired long-term potentiation (LTP). The latter could be fully rescued by pharmacological suppression of GluN1/GluN2B receptors, or by application of short soluble polySia fragments that inhibited opening of GluN1/GluN2B channels. These treatments and augmentation of synaptic NMDARs with the glycine transporter type 1 (GlyT1) inhibitor sarcosine also restored LTP in mice deficient in polysialyltransferase ST8SIA4. Furthermore, the impaired performance of polySia-deficient mice and two models of Alzheimer's disease in the mPFC-dependent cognitive tasks could be rescued by intranasal administration of polySia fragments. Our data demonstrate the essential role of polySia-NCAM in the balancing of signaling through synaptic/extrasynaptic NMDARs in mPFC and highlight the therapeutic potential of short polySia fragments to restrain GluN1/GluN2B-mediated signaling.

Dopaminergic neuromodulation of high gamma stimulus phase-locking in gerbil primary auditory cortex mediated by D1/D5-receptors.

Cortical release of the neurotransmitter dopamine has been implied in adapting cortical processing with respect to various functions including coding of stimulus salience, expectancy, error prediction, behavioral relevance and learning. Dopamine agonists have been shown to modulate recurrent cortico-thalamic feedback, and should therefore also affect synchronization and amplitude of thalamo-cortical oscillations. In this study, we have used multitaper spectral and time-frequency analysis of stimulus-evoked and spontaneous current source density patterns in primary auditory cortex of Mongolian gerbils to characterize dopaminergic neuromodulation of the oscillatory structure of current sources and sinks. We systemically applied D1/D5-receptor agonist SKF-38393 followed by competitive D1/D5-receptor antagonist SCH-23390. Our results reveal an increase in stimulus phase-locking in the high gamma-band (88-97 Hz) by SKF-38393, specifically in layers III/IV at the best frequency, which occurred at 20 ms after tone onset, and was reversed by SCH-23390. However, changes in induced oscillatory power after SKF-38393 treatment occurred stimulus-independently in the background activity in different layers than phase-locking effects and were not reversed by SCH-23390. These effects might either reflect longer-lasting changes in neural background noise, non-specific changes due to ketamine anesthesia, or an interaction of both. Without concomitant stimulus-induced power increase, increased stimulus phase-locking in layers III/IV indicates enhanced phase-resetting of neural oscillations by the stimulus after D1/D5-receptor activation. The frequency characteristics, together with the demonstrated stimulus specificity and layer specificity, suggest that changes in phase-resetting originate from dopaminergic neuromodulation of thalamo-cortical interactions. Enhanced phase-resetting might be a key step in the recruitment of cortical activity modes interpreting sensory input.

TOB is an effector of the hippocampus-mediated acute stress response.

Stress affects behavior and involves critical dynamic changes at multiple levels ranging from molecular pathways to neural circuits and behavior. Abnormalities at any of these levels lead to decreased stress resilience and pathological behavior. However, temporal modulation of molecular pathways underlying stress response remains poorly understood. Transducer of ErbB2.1, known as TOB, is involved in different physiological functions, including cellular stress and immediate response to stimulation. In this study, we investigated the role of TOB in psychological stress machinery at molecular, neural circuit, and behavioral levels. Interestingly, TOB protein levels increased after mice were exposed to acute stress. At the neural circuit level, functional magnetic resonance imaging (fMRI) suggested that intra-hippocampal and hippocampal-prefrontal connectivity were dysregulated in Tob knockout (Tob-KO) mice. Electrophysiological recordings in hippocampal slices showed increased postsynaptic AMPAR-mediated neurotransmission, accompanied by decreased GABA neurotransmission and subsequently altered Excitatory/Inhibitory balance after Tob deletion. At the behavioral level, Tob-KO mice show abnormal, hippocampus-dependent, contextual fear conditioning and extinction, and depression-like behaviors. On the other hand, increased anxiety observed in Tob-KO mice is hippocampus-independent. At the molecular level, we observed changes in factors involved in stress response like decreased stress-induced LCN2 expression and ERK phosphorylation, as well as increased MKP-1 expression. This study introduces TOB as an important modulator in the hippocampal stress signaling machinery. In summary, we reveal a molecular pathway and neural circuit mechanism by which Tob deletion contributes to expression of pathological stress-related behavior.

The extracellular matrix regulates cortical layer dynamics and cross-columnar frequency integration in the auditory cortex.

In the adult vertebrate brain, enzymatic removal of the extracellular matrix (ECM) is increasingly recognized to promote learning, memory recall, and restorative plasticity. The impact of the ECM on translaminar dynamics during cortical circuit processing is still not understood. Here, we removed the ECM in the primary auditory cortex (ACx) of adult Mongolian gerbils using local injections of hyaluronidase (HYase). Using laminar current-source density (CSD) analysis, we found layer-specific changes of the spatiotemporal synaptic patterns with increased cross-columnar integration and simultaneous weakening of early local sensory input processing within infragranular layers Vb. These changes had an oscillatory fingerprint within beta-band (25-36 Hz) selectively within infragranular layers Vb. To understand the laminar interaction dynamics after ECM digestion, we used time-domain conditional Granger causality (GC) measures to identify the increased drive of supragranular layers towards deeper infragranular layers. These results showed that ECM degradation altered translaminar cortical network dynamics with a stronger supragranular lead of the columnar response profile.

Lipopolysaccharide repeated challenge followed by chronic mild stress protocol introduces a combined model of depression in rats: reversibility by imipramine and pentoxifylline.

OBJECTIVES: The present study examined the effect of combined exposure to repeated challenge using low doses of lipopolysaccharide (LPS) and chronic mild stress (CMS) together. This combined exposure is thought to expose the animals to more realistic challenges, testable on different levels (behavioral, neurochemical, immunohistochemical and gene expression). The role of glial cells was examined, as well. Additionally, the effects of chronic administration of the tricyclic antidepressant imipramine and the anti-TNF-α pentoxyphylline were investigated. METHODS: Wistar rats were exposed to either repeated LPS (50µg/kg i.p.) over 2weeks, CMS protocol for 4weeks or LPS over 2weeks then 4weeks of CMS. Two groups of rats were exposed to LPS/CMS protocol and treated with either imipramine or pentoxifylline. Rats were examined for behavioral, neurochemical and gene expression changes. RESULTS: Animals exposed to LPS/CMS elaborated depressive-like symptoms with significant increase in both serum corticosterone and TNF-α levels compared to those in the saline, LPS or CMS groups. Hippocampal kynurenine/tryptophan ratio and TNF-α gene expression showed significant increase in the LPS/CMS model compared to those in saline, LPS or CMS groups. The immunohistochemical findings scrutinized the topography of the examined effects. Chronic treatment with imipramine or pentoxifylline significantly ameliorated the behavioral, neurochemical, immunohistochemical and TNF-α gene expression changes induced by the LPS/CMS protocol. CONCLUSION: This study gave a clue to the neurobiological processes underlying, at least, the subtypes of depressive disorders. It highlighted the possible interactions between stress and immune-inflammatory pathways in the pathogenesis of depression and suggested a new animal model of depression that addresses these pathways.