Dentate gyrus and CA3 GABAergic interneurons bidirectionally modulate signatures of internal and external drive to CA1.

Specific classes of GABAergic neurons play specific roles in regulating information processing in the brain. In the hippocampus, two major classes, parvalbumin-expressing (PV+) and somatostatin-expressing (SST+), differentially regulate endogenous firing patterns and target subcellular compartments of principal cells. How these classes regulate the flow of information throughout the hippocampus is poorly understood. We hypothesize that PV+ and SST+ interneurons in the dentate gyrus (DG) and CA3 differentially modulate CA3 patterns of output, thereby altering the influence of CA3 on CA1. We find that while suppressing either interneuron class increases DG and CA3 output, the effects on CA1 were very different. Suppressing PV+ interneurons increases local field potential signatures of coupling from CA3 to CA1 and decreases signatures of coupling from entorhinal cortex to CA1; suppressing SST+ interneurons has the opposite effect. Thus, DG and CA3 PV+ and SST+ interneurons bidirectionally modulate the flow of information through the hippocampal circuit.

Lamotrigine Attenuates Neuronal Excitability, Depresses GABA Synaptic Inhibition, and Modulates Theta Rhythms in Rat Hippocampus.

Theta oscillations generated in hippocampal (HPC) and cortical neuronal networks are involved in various aspects of brain function, including sensorimotor integration, movement planning, memory formation and attention. Disruptions of theta rhythms are present in individuals with brain disorders, including epilepsy and Alzheimer's disease. Theta rhythm generation involves a specific interplay between cellular (ion channel) and network (synaptic) mechanisms. HCN channels are theta modulators, and several medications are known to enhance their activity. We investigated how different doses of lamotrigine (LTG), an HCN channel modulator, and antiepileptic and neuroprotective agent, would affect HPC theta rhythms in acute HPC slices (in vitro) and anaesthetized rats (in vivo). Whole-cell patch clamp recordings revealed that LTG decreased GABAA-fast transmission in CA3 cells, in vitro. In addition, LTG directly depressed CA3 and CA1 pyramidal neuron excitability. These effects were partially blocked by ZD 7288, a selective HCN blocker, and are consistent with decreased excitability associated with antiepileptic actions. Lamotrigine depressed HPC theta oscillations in vitro, also consistent with its neuronal depressant effects. In contrast, it exerted an opposite, enhancing effect, on theta recorded in vivo. The contradictory in vivo and in vitro results indicate that LTG increases ascending theta activating medial septum/entorhinal synaptic inputs that over-power the depressant effects seen in HPC neurons. These results provide new insights into LTG actions and indicate an opportunity to develop more precise therapeutics for the treatment of dementias, memory disorders and epilepsy.

Modelling the spatial and temporal constrains of the GABAergic influence on neuronal excitability.

GABA (γ-amino butyric acid) is an inhibitory neurotransmitter in the adult brain that can mediate depolarizing responses during development or after neuropathological insults. Under which conditions GABAergic membrane depolarizations are sufficient to impose excitatory effects is hard to predict, as shunting inhibition and GABAergic effects on spatiotemporal filtering of excitatory inputs must be considered. To evaluate at which reversal potential a net excitatory effect was imposed by GABA (EGABAThr), we performed a detailed in-silico study using simple neuronal topologies and distinct spatiotemporal relations between GABAergic and glutamatergic inputs. These simulations revealed for GABAergic synapses located at the soma an EGABAThr close to action potential threshold (EAPThr), while with increasing dendritic distance EGABAThr shifted to positive values. The impact of GABA on AMPA-mediated inputs revealed a complex temporal and spatial dependency. EGABAThr depends on the temporal relation between GABA and AMPA inputs, with a striking negative shift in EGABAThr for AMPA inputs appearing after the GABA input. The spatial dependency between GABA and AMPA inputs revealed a complex profile, with EGABAThr being shifted to values negative to EAPThr for AMPA synapses located proximally to the GABA input, while for distally located AMPA synapses the dendritic distance had only a minor effect on EGABAThr. For tonic GABAergic conductances EGABAThr was negative to EAPThr over a wide range of gGABAtonic values. In summary, these results demonstrate that for several physiologically relevant situations EGABAThr is negative to EAPThr, suggesting that depolarizing GABAergic responses can mediate excitatory effects even if EGABA did not reach EAPThr.

Separable actions of acetylcholine and noradrenaline on neuronal ensemble formation in hippocampal CA3 circuits.

In the hippocampus, episodic memories are thought to be encoded by the formation of ensembles of synaptically coupled CA3 pyramidal cells driven by sparse but powerful mossy fiber inputs from dentate gyrus granule cells. The neuromodulators acetylcholine and noradrenaline are separately proposed as saliency signals that dictate memory encoding but it is not known if they represent distinct signals with separate mechanisms. Here, we show experimentally that acetylcholine, and to a lesser extent noradrenaline, suppress feed-forward inhibition and enhance Excitatory-Inhibitory ratio in the mossy fiber pathway but CA3 recurrent network properties are only altered by acetylcholine. We explore the implications of these findings on CA3 ensemble formation using a hierarchy of models. In reconstructions of CA3 pyramidal cells, mossy fiber pathway disinhibition facilitates postsynaptic dendritic depolarization known to be required for synaptic plasticity at CA3-CA3 recurrent synapses. We further show in a spiking neural network model of CA3 how acetylcholine-specific network alterations can drive rapid overlapping ensemble formation. Thus, through these distinct sets of mechanisms, acetylcholine and noradrenaline facilitate the formation of neuronal ensembles in CA3 that encode salient episodic memories in the hippocampus but acetylcholine selectively enhances the density of memory storage.

Synaptogenic activity of the axon guidance molecule Robo2 underlies hippocampal circuit function.

Synaptic connectivity within adult circuits exhibits a remarkable degree of cellular and subcellular specificity. We report that the axon guidance receptor Robo2 plays a role in establishing synaptic specificity in hippocampal CA1. In vivo, Robo2 is present and required postsynaptically in CA1 pyramidal neurons (PNs) for the formation of excitatory (E) but not inhibitory (I) synapses, specifically in proximal but not distal dendritic compartments. In vitro approaches show that the synaptogenic activity of Robo2 involves a trans-synaptic interaction with presynaptic Neurexins, as well as binding to its canonical extracellular ligand Slit. In vivo 2-photon Ca2+ imaging of CA1 PNs during spatial navigation in awake behaving mice shows that preventing Robo2-dependent excitatory synapse formation cell autonomously during development alters place cell properties of adult CA1 PNs. Our results identify a trans-synaptic complex linking the establishment of synaptic specificity to circuit function.

Conjunctive spatial and self-motion codes are topographically organized in the GABAergic cells of the lateral septum.

The hippocampal spatial code's relevance for downstream neuronal populations-particularly its major subcortical output the lateral septum (LS)-is still poorly understood. Here, using calcium imaging combined with unbiased analytical methods, we functionally characterized and compared the spatial tuning of LS GABAergic cells to those of dorsal CA3 and CA1 cells. We identified a significant number of LS cells that are modulated by place, speed, acceleration, and direction, as well as conjunctions of these properties, directly comparable to hippocampal CA1 and CA3 spatially modulated cells. Interestingly, Bayesian decoding of position based on LS spatial cells reflected the animal's location as accurately as decoding using the activity of hippocampal pyramidal cells. A portion of LS cells showed stable spatial codes over the course of multiple days, potentially reflecting long-term episodic memory. The distributions of cells exhibiting these properties formed gradients along the anterior-posterior and dorsal-ventral axes of the LS, directly reflecting the topographical organization of hippocampal inputs to the LS. Finally, we show using transsynaptic tracing that LS neurons receiving CA3 and CA1 excitatory input send projections to the hypothalamus and medial septum, regions that are not targeted directly by principal cells of the dorsal hippocampus. Together, our findings demonstrate that the LS accurately and robustly represents spatial, directional as well as self-motion information and is uniquely positioned to relay this information from the hippocampus to its downstream regions, thus occupying a key position within a distributed spatial memory network.

Serine/Threonine Phosphatases in LTP: Two B or Not to Be the Protein Synthesis Blocker-Induced Impairment of Early Phase.

Dephosphorylation of target proteins at serine/threonine residues is one of the most crucial mechanisms regulating their activity and, consequently, the cellular functions. The role of phosphatases in synaptic plasticity, especially in long-term depression or depotentiation, has been reported. We studied serine/threonine phosphatase activity during the protein synthesis blocker (PSB)-induced impairment of long-term potentiation (LTP). Established protein phosphatase 2B (PP2B, calcineurin) inhibitor cyclosporin A prevented the LTP early phase (E-LTP) decline produced by pretreatment of hippocampal slices with cycloheximide or anisomycin. For the first time, we directly measured serine/threonine phosphatase activity during E-LTP, and its significant increase in PSB-treated slices was demonstrated. Nitric oxide (NO) donor SNAP also heightened phosphatase activity in the same manner as PSB, and simultaneous application of anisomycin + SNAP had no synergistic effect. Direct measurement of the NO production in hippocampal slices by the NO-specific fluorescent probe DAF-FM revealed that PSBs strongly stimulate the NO concentration in all studied brain areas: CA1, CA3, and dentate gyrus (DG). Cyclosporin A fully abolished the PSB-induced NO production in the hippocampus, suggesting a close relationship between nNOS and PP2B activity. Surprisingly, cyclosporin A alone impaired short-term plasticity in CA1 by decreasing paired-pulse facilitation, which suggests bi-directionality of the influences of PP2B in the hippocampus. In conclusion, we proposed a minimal model of signaling events that occur during LTP induction in normal conditions and the PSB-treated slices.

Distinct place cell dynamics in CA1 and CA3 encode experience in new environments.

When exploring new environments animals form spatial memories that are updated with experience and retrieved upon re-exposure to the same environment. The hippocampus is thought to support these memory processes, but how this is achieved by different subnetworks such as CA1 and CA3 remains unclear. To understand how hippocampal spatial representations emerge and evolve during familiarization, we performed 2-photon calcium imaging in mice running in new virtual environments and compared the trial-to-trial dynamics of place cells in CA1 and CA3 over days. We find that place fields in CA1 emerge rapidly but tend to shift backwards from trial-to-trial and remap upon re-exposure to the environment a day later. In contrast, place fields in CA3 emerge gradually but show more stable trial-to-trial and day-to-day dynamics. These results reflect different roles in CA1 and CA3 in spatial memory processing during familiarization to new environments and constrain the potential mechanisms that support them.

Neurexins regulate presynaptic GABAB-receptors at central synapses.

Diverse signaling complexes are precisely assembled at the presynaptic active zone for dynamic modulation of synaptic transmission and synaptic plasticity. Presynaptic GABAB-receptors nucleate critical signaling complexes regulating neurotransmitter release at most synapses. However, the molecular mechanisms underlying assembly of GABAB-receptor signaling complexes remain unclear. Here we show that neurexins are required for the localization and function of presynaptic GABAB-receptor signaling complexes. At four model synapses, excitatory calyx of Held synapses in the brainstem, excitatory and inhibitory synapses on hippocampal CA1-region pyramidal neurons, and inhibitory basket cell synapses in the cerebellum, deletion of neurexins rendered neurotransmitter release significantly less sensitive to GABAB-receptor activation. Moreover, deletion of neurexins caused a loss of GABAB-receptors from the presynaptic active zone of the calyx synapse. These findings extend the role of neurexins at the presynaptic active zone to enabling GABAB-receptor signaling, supporting the notion that neurexins function as central organizers of active zone signaling complexes.

Coincident glutamatergic depolarizations enhance GABAA receptor-dependent Cl- influx in mature and suppress Cl- efflux in immature neurons.

The impact of GABAergic transmission on neuronal excitability depends on the Cl--gradient across membranes. However, the Cl--fluxes through GABAA receptors alter the intracellular Cl- concentration ([Cl-]i) and in turn attenuate GABAergic responses, a process termed ionic plasticity. Recently it has been shown that coincident glutamatergic inputs significantly affect ionic plasticity. Yet how the [Cl-]i changes depend on the properties of glutamatergic inputs and their spatiotemporal relation to GABAergic stimuli is unknown. To investigate this issue, we used compartmental biophysical models of Cl- dynamics simulating either a simple ball-and-stick topology or a reconstructed CA3 neuron. These computational experiments demonstrated that glutamatergic co-stimulation enhances GABA receptor-mediated Cl- influx at low and attenuates or reverses the Cl- efflux at high initial [Cl-]i. The size of glutamatergic influence on GABAergic Cl--fluxes depends on the conductance, decay kinetics, and localization of glutamatergic inputs. Surprisingly, the glutamatergic shift in GABAergic Cl--fluxes is invariant to latencies between GABAergic and glutamatergic inputs over a substantial interval. In agreement with experimental data, simulations in a reconstructed CA3 pyramidal neuron with physiological patterns of correlated activity revealed that coincident glutamatergic synaptic inputs contribute significantly to the activity-dependent [Cl-]i changes. Whereas the influence of spatial correlation between distributed glutamatergic and GABAergic inputs was negligible, their temporal correlation played a significant role. In summary, our results demonstrate that glutamatergic co-stimulation had a substantial impact on ionic plasticity of GABAergic responses, enhancing the attenuation of GABAergic inhibition in the mature nervous systems, but suppressing GABAergic [Cl-]i changes in the immature brain. Therefore, glutamatergic shift in GABAergic Cl--fluxes should be considered as a relevant factor of short-term plasticity.

Metabotropic Glutamate Receptors at the Aged Mossy Fiber - CA3 Synapse of the Hippocampus.

Metabotropic glutamate receptors (mGluRs) are a group of G-protein-coupled receptors that exert a broad array of modulatory actions at excitatory synapses of the central nervous system. In the hippocampus, the selective activation of the different mGluRs modulates the intrinsic excitability, the strength of synaptic transmission, and induces multiple forms of long-term plasticity. Despite the relevance of mGluRs in the normal function of the hippocampus, we know very little about the changes that mGluRs functionality undergoes during the non-pathological aging. Here, we review data concerning the physiological actions of mGluRs, with particular emphasis on hippocampal area CA3. Later, we examine changes in the expression and functionality of mGluRs during the aging process. We complement this review with original data showing an array of electrophysiological modifications observed in the synaptic transmission and intrinsic excitability of aged CA3 pyramidal cells in response to the pharmacological stimulation of the different mGluRs.

Enhancing adult neurogenesis promotes contextual fear memory discrimination and activation of hippocampal-dorsolateral septal circuits.

Hippocampal circuitry is continuously modified by integration of adult-born dentate granule cells (DGCs). Prior work has shown that enhancing adult hippocampal neurogenesis decreases interference or overlap or conflict between ensembles of similar contexts and promotes discrimination of a shock-associated context from a similar, neutral context. However, the impact of enhanced integration of adult-born neurons on hippocampal network activity or downstream circuits such as the dorsolateral septum that mediate defensive behavioral responses is poorly understood. Here, we first replicated our finding that genetic expansion of the population of adult-born dentate granule cells (8 weeks and younger) promotes contextual fear discrimination. We found that enhanced contextual fear discrimination is associated with greater c-Fos expression in discrete hippocampal subfields along the proximo-distal and dorsoventral axis. Examination of the dorsolateral septum revealed an increase in activation of somatostatin expressing neurons consistent with recent characterization of these cells as calibrators of defensive behavior. Together, these findings begin to shed light on how genetically enhancing adult hippocampal neurogenesis affects activity of hippocampal-dorsolateral septal circuits.

REV-ERBα mediates complement expression and diurnal regulation of microglial synaptic phagocytosis.

The circadian clock regulates various aspects of brain health including microglial and astrocyte activation. Here, we report that deletion of the master clock protein BMAL1 in mice robustly increases expression of complement genes, including C4b and C3, in the hippocampus. BMAL1 regulates expression of the transcriptional repressor REV-ERBα, and deletion of REV-ERBα causes increased expression of C4b transcript in neurons and astrocytes as well as C3 protein primarily in astrocytes. REV-ERBα deletion increased microglial phagocytosis of synapses and synapse loss in the CA3 region of the hippocampus. Finally, we observed diurnal variation in the degree of microglial synaptic phagocytosis which was antiphase to REV-ERBα expression. This daily variation in microglial synaptic phagocytosis was abrogated by global REV-ERBα deletion, which caused persistently elevated synaptic phagocytosis. This work uncovers the BMAL1-REV-ERBα axis as a regulator of complement expression and synaptic phagocytosis in the brain, linking circadian proteins to synaptic regulation.

Space-Dependent Glia-Neuron Interplay in the Hippocampus of Transgenic Models of ß-Amyloid Deposition.

This review is focused on the description and discussion of the alterations of astrocytes and microglia interplay in models of Alzheimer's disease (AD). AD is an age-related neurodegenerative pathology with a slowly progressive and irreversible decline of cognitive functions. One of AD's histopathological hallmarks is the deposition of amyloid beta (Aß) plaques in the brain. Long regarded as a non-specific, mere consequence of AD pathology, activation of microglia and astrocytes is now considered a key factor in both initiation and progression of the disease, and suppression of astrogliosis exacerbates neuropathology. Reactive astrocytes and microglia overexpress many cytokines, chemokines, and signaling molecules that activate or damage neighboring cells and their mutual interplay can result in virtuous/vicious cycles which differ in different brain regions. Heterogeneity of glia, either between or within a particular brain region, is likely to be relevant in healthy conditions and disease processes. Differential crosstalk between astrocytes and microglia in CA1 and CA3 areas of the hippocampus can be responsible for the differential sensitivity of the two areas to insults. Understanding the spatial differences and roles of glia will allow us to assess how these interactions can influence the state and progression of the disease, and will be critical for identifying therapeutic strategies.

Copper Ions Reduce the Effect of Protons on Desensitization of Glycine Receptors.

Chloride current (IGly) evoked by the rapid (600 msec) application of glycine on isolated pyramidal neurons of the rat hippocampus was recorded using the patch clamp technique. We studied the effect of individual or combined application of copper ions (Cu2+) and protons (H+) on IGly. It was found that both Cu2+ (10 µM) and H+ (pH 7.0 and 6.0) applied separately caused a fast and reversible effect on IGly that included two components: a decrease in peak amplitude (Ipeak) and a decrease in the desensitization time constant (τdes). During combined application, the effects on Ipeak were additive, which indicates the independence of the mechanisms of these effects. At the same time, the effect of combined application of Cu2+ and H+ on τdes was not additive and sometimes a slowdown of the total desensitization was observed. The latter result suggests that H+ and Cu2+ can play the role of mutual antagonists when they affect the desensitization of GlyR.

Class switching of carbonic anhydrase isoforms mediates remyelination in CA3 hippocampal neurons during chronic hypoxia.

Chronic exposure to hypoxia results in cerebral white matter hyperintensities, increased P300 latency, delayed response and impairment in working memory. Despite burgeoning evidence on role of myelination in nerve conduction, the effect of chronic hypoxia on myelination of hippocampal neurons has been less studied. The present study provides novel evidence on alterations in myelination of hippocampal CA3 neurons following chronic hypoxic exposure. Sprague Dawley rats exposed to global hypobaric hypoxia simulating altitude of 25,000 ft showed progressive demyelination in CA3 hippocampal neurons on 14 days followed by remyelination on 21 and 28 days. The demyelination of CA3 neurons was associated with increased apoptosis of both oligodendrocyte precursor cells (OPCs) and mature oligodendrocytes (OLs), peroxidation of myelin lipids, and nitration induced reduced expression of Carbonic Anhydrase II (CAII). Prolonged hypoxic exposure of 21 and 28 days on the other hand resulted in peroxisome proliferator-activated receptor alpha (PPARα) induced upregulation of Carbonic Anhydrase IV (CAIV) expression in mature oligodendrocytes through iNOS mediated mechanisms along with reduction in lipid peroxidation and remyelination. Inhibition of carbonic anhydrase activity on the other hand prevented remyelination of CA3 neurons. Based on these findings we propose a novel iNOS mediated mechanism for regulation of myelination in hypoxic hippocampal neurons through class switching of carbonic anhydrases.

Topographic heterogeneity of intrinsic excitability in mouse hippocampal CA3 pyramidal neurons.

Area CA3 in the hippocampus is traditionally thought to act as a homogeneous neural circuit that is vital for spatial navigation and episodic memories. However, recent studies have revealed that CA3 pyramidal neurons in dorsal hippocampus display marked anatomic and functional heterogeneity along the proximodistal (transverse) axis. The hippocampus is also known to be functionally segregated along the dorsoventral (longitudinal) axis, with dorsal hippocampus strongly involved in spatial navigation and ventral hippocampus associated with emotion and anxiety. Surprisingly, however, relatively little is known about CA3 functional heterogeneity along the dorsoventral axis. Here, we carried out mouse-brain-slice patch-clamp recordings and morphological analyses to examine the heterogeneity of CA3 cellular properties along both proximodistal and dorsoventral axes. We find that CA3 pyramidal neurons exhibit considerable heterogeneity of somatodendritic morphology and intrinsic membrane properties, with ventral CA3 (vCA3) displaying more elaborate somatodendritic morphology, lower intrinsic excitability, smaller input resistance, greater cell capacitance, and more prominent hyperpolarization-activated current than dorsal CA3 (dCA3). Furthermore, although both dCA3 and vCA3 exhibit proximal-to-distal gradients in intrinsic properties and neuronal morphology, these proximal-to-distal gradients in vCA3 are more moderate than those in dCA3. Taken together, our results extend previous findings on the proximodistal heterogeneity of dCA3 function and uncover a complex, yet orderly, pattern of topographic organization of CA3 neuronal features that extends to multiple anatomic dimensions and may contribute to its in vivo functional diversity.NEW & NOTEWORTHY Area CA3 is a major hippocampal region that is classically thought to act as a homogeneous neural network vital for spatial navigation and episodic memories. Here, we report that CA3 pyramidal neurons exhibit marked heterogeneity of somatodendritic morphology and cellular electrical properties along both proximodistal and dorsoventral axes. These new results uncover a complex, yet orderly, pattern of topographic organization of CA3 neuronal features that may contribute to its in vivo functional diversity.

Parvalbumin and Somatostatin Interneurons Contribute to the Generation of Hippocampal Gamma Oscillations.

γ-frequency oscillations (30-120 Hz) in cortical networks influence neuronal encoding and information transfer, and are disrupted in multiple brain disorders. While synaptic inhibition is important for synchronization across the γ-frequency range, the role of distinct interneuronal subtypes in slow (<60 Hz) and fast γ states remains unclear. Here, we used optogenetics to examine the involvement of parvalbumin-expressing (PV+) and somatostatin-expressing (SST+) interneurons in γ oscillations in the mouse hippocampal CA3 ex vivo, using animals of either sex. Disrupting either PV+ or SST+ interneuron activity, via either photoinhibition or photoexcitation, led to a decrease in the power of cholinergically induced slow γ oscillations. Furthermore, photoexcitation of SST+ interneurons induced fast γ oscillations, which depended on both synaptic excitation and inhibition. Our findings support a critical role for both PV+ and SST+ interneurons in slow hippocampal γ oscillations, and further suggest that intense activation of SST+ interneurons can enable the CA3 circuit to generate fast γ oscillations.SIGNIFICANCE STATEMENT The generation of hippocampal γ oscillations depends on synchronized inhibition provided by GABAergic interneurons. Parvalbumin-expressing (PV+) interneurons are thought to play the key role in coordinating the spike timing of excitatory pyramidal neurons, but the role distinct inhibitory circuits in network synchronization remains unresolved. Here, we show, for the first time, that causal disruption of either PV+ or somatostatin-expressing (SST+) interneuron activity impairs the generation of slow γ oscillations in the ventral hippocampus ex vivo We further show that SST+ interneuron activation along with general network excitation is sufficient to generate high-frequency γ oscillations in the same preparation. These results affirm a crucial role for both PV+ and SST+ interneurons in hippocampal γ oscillation generation.

Selective Routing of Spatial Information Flow from Input to Output in Hippocampal Granule Cells.

Dentate gyrus granule cells (GCs) connect the entorhinal cortex to the hippocampal CA3 region, but how they process spatial information remains enigmatic. To examine the role of GCs in spatial coding, we measured excitatory postsynaptic potentials (EPSPs) and action potentials (APs) in head-fixed mice running on a linear belt. Intracellular recording from morphologically identified GCs revealed that most cells were active, but activity level varied over a wide range. Whereas only ∼5% of GCs showed spatially tuned spiking, ∼50% received spatially tuned input. Thus, the GC population broadly encodes spatial information, but only a subset relays this information to the CA3 network. Fourier analysis indicated that GCs received conjunctive place-grid-like synaptic input, suggesting code conversion in single neurons. GC firing was correlated with dendritic complexity and intrinsic excitability, but not extrinsic excitatory input or dendritic cable properties. Thus, functional maturation may control input-output transformation and spatial code conversion.

The neuroprotective effect of curcumin against Cd-induced neurotoxicity and hippocampal neurogenesis promotion through CREB-BDNF signaling pathway.

Heavy metal neurotoxicity is one of the major challenges in today's era due to the large scale and widespread mechanisation of the production. However, the causative factors responsible for neurotoxicity are neither known nor do we have the availability of therapeutic approaches to deal with it. One of the major causative agents of neurotoxicity is a non-essential transition heavy metal, Cadmium (Cd), that reaches the central nervous system (CNS) through the nasal mucosa and olfactory pathway causing adverse structural and functional effects. In this study, we explored the neuroprotective efficacy of plant derived Curcumin which is reported to have pleiotropic biological activity including anti-oxidant, anti-inflammatory, anti-apoptotic, anti-carcinogenic and anti-angiogenic effects. Four different concentrations of curcumin (20, 40, 80 and 160 mg/kg of the body weight) were used to assess the behavioural, biochemical, hippocampal proteins (BDNF, CREB, DCX and Synapsin II) and histological changes in Swiss Albino mice that were pre-treated with Cd (2.5 mg/kg). The findings showed that Cd exposure led to the behavioural impairment through oxidative stress, reduction of hippocampal neurogenesis associated proteins, and degeneration of CA3 and cortical neurons. However, treatment of different curcumin concentrations had effectively restored the behavioural changes in Cd-exposed mice through regulation of oxidative stress and up-regulation of hippocampal proteins in a dose-dependent manner. Significantly, a dose of 160 mg/kg body weight was found to be glaringly effective. From this study, we infer that curcumin reverses the adverse effects of neurotoxicity induced by Cd and promotes neurogenesis.