Swananda Marathe

α2-adrenoceptor blockade accelerates the neurogenic, neurotrophic, and behavioral effects of chronic antidepressant treatment

Slow-onset adaptive changes that arise from sustained antidepressant treatment, such as enhanced adult hippocampal neurogenesis and increased trophic factor expression, play a key role in the behavioral effects of antidepressants. α2-Adrenoceptors contribute to the modulation of mood and are potential targets for the development of faster acting antidepressants. We investigated the influence of α2-adrenoceptors on adult hippocampal neurogenesis. Our results indicate that α2-adrenoceptor agonists, clonidine and guanabenz, decrease adult hippocampal neurogenesis through a selective effect on the proliferation, but not the survival or differentiation, of progenitors. These effects persist in dopamine β-hydroxylase knock-out (Dbh−/−) mice lacking norepinephrine, supporting a role for α2-heteroceptors on progenitor cells, rather than α2-autoreceptors on noradrenergic neurons that inhibit norepinephrine release. Adult hippocampal progenitors in vitro express all the α2-adrenoceptor subtypes, and decreased neurosphere frequency and BrdU incorporation indicate direct effects of α2-adrenoceptor stimulation on progenitors. Furthermore, coadministration of the α2-adrenoceptor antagonist yohimbine with the antidepressant imipramine significantly accelerates effects on hippocampal progenitor proliferation, the morphological maturation of newborn neurons, and the increase in expression of brain derived neurotrophic factor and vascular endothelial growth factor implicated in the neurogenic and behavioral effects of antidepressants. Finally, short-duration (7 d) yohimbine and imipramine treatment results in robust behavioral responses in the novelty suppressed feeding test, which normally requires 3 weeks of treatment with classical antidepressants. Our results demonstrate that α2-adrenoceptors, expressed by progenitor cells, decrease adult hippocampal neurogenesis, while their blockade speeds up antidepressant action, highlighting their importance as targets for faster acting antidepressants.

Notch signaling in the brain: in good and bad times.

Notch signaling is an evolutionarily conserved pathway, which is fundamental for neuronal development and specification. In the last decade, increasing evidence has pointed out an important role of this pathway beyond embryonic development, indicating that Notch also displays a critical function in the mature brain of vertebrates and invertebrates. This pathway appears to be involved in neural progenitor regulation, neuronal connectivity, synaptic plasticity and learning/memory. In addition, Notch appears to be aberrantly regulated in neurodegenerative diseases, including Alzheimers disease and ischemic injury. The molecular mechanisms by which Notch displays these functions in the mature brain are not fully understood, but are currently the subject of intense research. In this review, we will discuss old and novel Notch targets and molecular mediators that contribute to Notch function in the mature brain and will summarize recent findings that explore the two facets of Notch signaling in brain physiology and pathology.

Notch1 regulates hippocampal plasticity through interaction with the reelin pathway, glutamatergic transmission and CREB signaling

Notch signaling plays a crucial role in adult brain function such as synaptic plasticity, memory and olfaction. Several reports suggest an involvement of this pathway in neurodegenerative dementia. Yet, to date, the mechanism underlying Notch activity in mature neurons remains unresolved. In this work, we investigate how Notch regulates synaptic potentiation and contributes to the establishment of memory in mice. We observe that Notch1 is a postsynaptic receptor with functional interactions with the Reelin receptor, apolipoprotein E receptor 2 (ApoER2) and the ionotropic receptor, N-methyl-D-aspartate receptor (NMDAR). Targeted loss of Notch1 in the hippocampal CA fields affects Reelin signaling by influencing Dab1 expression and impairs the synaptic potentiation achieved through Reelin stimulation. Further analysis indicates that loss of Notch1 affects the expression and composition of the NMDAR but not AMPAR. Glutamatergic signaling is further compromised through downregulation of CamKII and its secondary and tertiary messengers resulting in reduced cAMP response element-binding (CREB) signaling. Our results identify Notch1 as an important regulator of mechanisms involved in synaptic plasticity and memory formation. These findings emphasize the possible involvement of this signaling receptor in dementia. Highlights In this paper, we propose a mechanism for Notch1-dependent plasticity that likely underlies the function of Notch1 in memory formation: Notch1 interacts with another important developmental pathway, the Reelin cascade. Notch1 regulates both NMDAR expression and composition. Notch1 influences a cascade of cellular events culminating in CREB activation.

Notch signaling in response to excitotoxicity induces neurodegeneration via erroneous cell cycle reentry

Neurological disorders such as Alzheimer’s disease, stroke and epilepsy are currently marred by the lack of effective treatments to prevent neuronal death. Erroneous cell cycle reentry (CCR) is hypothesized to have a causative role in neurodegeneration. We show that forcing S-phase reentry in cultured hippocampal neurons is sufficient to induce neurodegeneration. We found that kainic-acid treatment in vivo induces erroneous CCR and neuronal death through a Notch-dependent mechanism. Ablating Notch signaling in neurons provides neuroprotection against kainic acid-induced neuronal death. We further show that kainic-acid treatment activates Notch signaling, which increases the bioavailability of CyclinD1 through Akt/GSK3β pathway, leading to aberrant CCR via activation of CyclinD1-Rb-E2F1 axis. In addition, pharmacological blockade of this pathway at critical steps is sufficient to confer resistance to kainic acid-induced neurotoxicity in mice. Taken together, our results demonstrate that excitotoxicity leads to neuronal death in a Notch-dependent manner through erroneous CCR.

Notch1 activity in the olfactory bulb is odour-dependent and contributes to olfactory behaviour

Notch signalling plays an important role in synaptic plasticity, learning and memory functions in both Drosophila and rodents. In this paper, we report that this feature is not restricted to hippocampal networks but also involves the olfactory bulb (OB). Odour discrimination and olfactory learning in rodents are essential for survival. Notch1 expression is enriched in mitral cells of the mouse OB. These principal neurons are responsive to specific input odorants and relay the signal to the olfactory cortex. Olfactory stimulation activates a subset of mitral cells, which show an increase in Notch activity. In Notch1cKOKln mice, the loss of Notch1 in mitral cells affects the magnitude of the neuronal response to olfactory stimuli. In addition, Notch1cKOKln mice display reduced olfactory aversion to propionic acid as compared to wildtype controls. This indicates, for the first time, that Notch1 is involved in olfactory processing and may contribute to olfactory behaviour.

Notch in memories: Points to remember.

Memory is a temporally evolving molecular and structural process, which involves changes from local synapses to complex neural networks. There is increasing evidence for an involvement of developmental pathways in regulating synaptic communication in the adult nervous system. Notch signaling has been implicated in memory formation in a variety of species. Nevertheless, the mechanism of Notch underlying memory consolidation remains poorly understood. In this commentary, besides offering an overview of the advances in the field of Notch in memory, we highlight some of the weaknesses of the studies and attempt to cast light on the apparent discrepancies on the role of Notch in memory. We believe that future studies, employing high‐throughput technologies and targeted Notch loss and gain of function animal models, will reveal the mechanisms of Notch dependent plasticity and resolve whether this signaling pathway is implicated in the cognitive deficit associated with dementia.

Jagged1 Is Altered in Alzheimer's Disease and Regulates Spatial Memory Processing

Notch signaling plays an instrumental role in hippocampus-dependent memory formation and recent evidence indicates a displacement of Notch1 and a reduction its activity in hippocampal and cortical neurons from Alzheimers disease (AD) patients. As Notch activation depends on ligand availability, we investigated whether Jagged1 expression was altered in brain specimen of AD patients. We found that Jagged1 expression was reduced in the CA fields and that there was a gradual reduction of Jagged1 in the cerebrospinal fluid (CSF) with the progression of dementia. Given the role of Notch signaling in memory encoding, we investigated whether targeted loss of Jagged1 in neurons may be responsible for the memory loss seen in AD patients. Using a transgenic mouse model, we show that the targeted loss of Jagged1 expression during adulthood is sufficient to cause spatial memory loss and a reduction in exploration-dependent Notch activation. We also show that Jagged1 is selectively enriched at the presynaptic terminals in mice. Overall, the present data emphasizes the role of the Notch ligand, Jagged1, in memory formation and the potential deficit of the signaling ligand in AD patients.

Notch in memories: Points to remember: Notch in Memories: Points to Remember

Memory is a temporally evolving molecular and structural process, which involves changes from local synapses to complex neural networks. There is increasing evidence for an involvement of developmental pathways in regulating synaptic communication in the adult nervous system. Notch signaling has been implicated in memory formation in a variety of species. Nevertheless, the mechanism of Notch in memory consolidation remains poorly understood. In this commentary, besides offering an overview of the advances in the field of Notch in memory, we highlight some of the weaknesses of the studies and attempt to cast light on some of the apparent discrepancies on the role of Notch in memory. We believe that future studies, employing high‐throughput technologies and targeted Notch loss and gain of function animal models, will reveal the mechanisms of Notch‐dependent plasticity and resolve whether this signaling pathway is implicated in the cognitive deficit associated with dementia.

Monitoring Notch activity in the mouse.

Several laboratories have developed genetic methods to monitor Notch activity in developing and adult mice. These approaches have been useful in identifying Notch signaling with high temporal and spatial resolution. This research has contributed substantially to our understanding of the role of Notch in cell specification and cellular physiology. Here, we present two protocols to monitor Notch activity in the mouse brain: (1) by intraventricular electroporation and (2) by intracranial viral injections of Notch reporter constructs. These methods allow monitoring of Notch signaling in specific brain regions from development to adulthood. In addition, using the appropriate modifications, the Notch reporter systems can also be used to monitor Notch activity in other organs of the mouse such as retina, skin, skeletal muscle, and cancer cells.

PARADOXICAL EFFECTS OF NOTCH SIGNALING IN RESPONSE TO ENVIRONMENTAL ENRICHMENT DURING CRITICAL PERIOD: MOLECULAR MECHANISM UNDERLYING COGNITIVE RESERVE?

Background: Adult neurogenesis and hippocampal function are both regulated by neuronal activity, particularly by GABAergic signals. Recently, it has been reported that an imbalance of the GABAergic ~a transmission impairs adult neurogenesis in Alzheimer’s disease (AD). This GABAergic signal is modulated by several endogenous molecules. Diazepam binding inhibitor is a small cytosolic polypeptide which is an inverse agonist of GABA A receptor. Thus, we researched the expression and the effect of diazepam binding inhibitor (DBI) on neurogenesis in the hippocampus by using AD model mice. Methods: In this study, we used AD model mice which the early onset of the symptoms of AD was induced. Our recent study showed that feeding with High Fat Diet is a viable method for inducing the early onset of the symptoms of AD in B6C3-Tg (APPswe/PSEN1dE9)85Dbo/J Alzheimer’s Disease Model Transgenic mice. Using these mice, we performed DBI knockdown experiment and immunostaing of DBI to investigate a functional role of DBI in dentate gyrus. To evaluate the effect of DBI knockdown for differentiation we observed the number and morphology of doublecortin (DCX; immature neuron marker) positive cells. Results: We immunostained DBI and dyed senile plaques to compare the expression of DBI in AD model and control mice. As a result, we observed a tendency of increased DBI expression in the hippocampus in AD model mice. Commonly, DBI is expressed in neural stem cells, however, it was also expressed in glial cell in AD model mice. Furthermore, expression of DBI was observed in astrocytes surrounding senile plaques in AD model mice. This result corroborates the report that the Ab peptide stimulates DBI biosynthesis in cultured rat astrocytes. The impairment of maturation of immature neuron in AD model mice was repaired by the inhibition of DBI expression in the dentate gyrus. Conclusions: These results suggest that increased DBI in the hippocampus inhibit normal maturation in AD model mice. This increased DBI is derived from astrocyte activated by Ab. DBI produced by astrocyte and released in the dentate gyrus cause disorder in neurogenesis in AD mice via GABA A receptor.