A hippocampus dependent neural circuit loop underlying the generation of auditory mismatch negativity.

Extracting relevant information and transforming it into appropriate behavior, is a fundamental brain function, and requires the coordination between the sensory and cognitive systems, however, the underlying mechanisms of interplay between sensory and cognition systems remain largely unknown. Here, we developed a mouse model for mimicking human auditory mismatch negativity (MMN), a well-characterized translational biomarker for schizophrenia, and an index of early auditory information processing. We found that a subanesthetic dose of ketamine decreased the amplitude of MMN in adult mice. Using pharmacological and chemogenetic approaches, we identified an auditory cortex-entorhinal cortex-hippocampus neural circuit loop that is required for the generation of MMN. In addition, we found that inhibition of dCA1→MEC circuit impaired the auditory related fear discrimination. Moreover, we found that ketamine induced MMN deficiency by inhibition of long-range GABAergic projection from the CA1 region of the dorsal hippocampus to the medial entorhinal cortex. These results provided circuit insights for ketamine effects and early auditory information processing. As the entorhinal cortex is the interface between the neocortex and hippocampus, and the hippocampus is critical for the formation, consolidation, and retrieval of episodic memories and other cognition, our results provide a neural mechanism for the interplay between the sensory and cognition systems.

Ellagic Acid Modulates the Amyloid Precursor Protein Gene via Superoxide Dismutase Regulation in the Entorhinal Cortex in an Experimental Alzheimer's Model.

Patients suffering from Alzheimer's disease (AD) are still increasing worldwide. The development of (AD) is related to oxidative stress and genetic factors. This study investigated the therapeutic effects of ellagic acid (EA) on the entorhinal cortex (ERC), which plays a major role in episodic memory, in the brains of an AD rat model. AD was induced using AlCl3 (50 mg/kg orally for 4 weeks). Rats were divided into four groups: control, AD model, EA (treated with 50 mg/kg EA orally for 4 weeks), and ADEA (AD rats treated with EA after AlCl3 was stopped) groups. All rats were investigated for episodic memory using the novel object recognition test (NORT), antioxidant serum biomarkers, lipid peroxidation, histopathology of the ERC, and quantitative PCR for the superoxide dismutase (SOD) gene. EA therapy in AD rats significantly increased the discrimination index for NORT and the levels of SOD, glutathione, and total antioxidant capacity. Lipid peroxidation products were decreased, and the neurofibrillary tangles and neuritic plaques in the ERC sections were reduced after EA administration. The decrease in ERC thickness in the AD group, caused by caspase-3-mediated apoptosis and neurotoxicity due to amyloid precursor protein, was modulated by the increased SOD mRNA expression. Adjustment of the ERC antioxidant environment and decreased oxidative stress under EA administration enhanced SOD expression, resulting in the modulation of amyloid precursor protein toxicity and caspase-3-mediated apoptosis, thereby restoring episodic memory.

Prenatal sevoflurane exposure causes abnormal development of the entorhinal cortex in rat offspring.

As a gamma-aminobutyric acid type A receptor agonist sevoflurane is a common general anesthetic used in anesthesia and affects the neural development in offspring. We hypothesized that sevoflurane could regulate interneurons via the neuregulin-1-epidermal growth factor receptor-4 (NRG1-ErbB4) pathway in the entorhinal cortex (ECT) of the middle pregnancy. Six female rats in middle pregnancy (14.5 days of pregnancy) were randomly and equally divided into sevoflurane (SeV) and control groups. The rats in the SeV group were exposed to 4% sevoflurane for 3 hours. The expression levels of NRG1 and ErbB4, parvalbumin (PV) and glutamic acid decarboxylase (GAD67), and N-methyl-D-aspartate receptor subunit 2A (NR2A) and subunit 2B (NR2B) in offspring were examined through immunohistochemistry. The pyramidal neurons in the ECT were examined via Golgi staining. The levels of NRG1 and ErbB4 were significantly decreased (P < 0.01) and the levels of PV and GAD67 (interneurons) were found to be decreased in the SeV group (P < 0.01). The level of NR2B was found to be increased while the level of NR2A being decreased in the SeV group (P < 0.01). The development of pyramidal neurons was abnormal in the SeV group (P < 0.05). Conclusively, prenatal sevoflurane exposure could lead to the disturbance of the interneurons by activating the NRG1-ErbB4 pathway and subsequently result in abnormal development of pyramidal neurons in middle pregnancy. Prenatal sevoflurane exposure in middle pregnancy could be potentially harmful to the neural development of rat offspring. This study may reveal a novel pathway in the influence mechanism of sevoflurane on rat offspring.

Memantine ameliorates cognitive deficit in AD mice via enhancement of entorhinal-CA1 projection.

BACKGROUND: Memantine, a low- to moderate-affinity uncompetitive N-methyl-D-aspartate receptor antagonist, has been shown to improve cognitive functions in animal models of Alzheimer's disease (AD). Here we treated APP/PS1 AD mice with a therapeutic dose of memantine (20 mg/kg/day) and examined its underlying mechanisms in ameliorating cognitive defects. METHODS: Using behavioral, electrophysiological, optogenetic and morphology approaches to explore how memantine delay the pathogenesis of AD. RESULTS: Memantine significantly improved the acquisition in Morris water maze (MWM) in APP/PS1 mice without affecting the speed of swimming. Furthermore, memantine enhanced EC to CA1 synaptic neurotransmission and promoted dendritic spine regeneration of EC neurons that projected to CA1. CONCLUSIONS: Our study reveals the underlying mechanism of memantine in the treatment of AD mice.

2-Pentadecyl-2-oxazoline ameliorates memory impairment and depression-like behaviour in neuropathic mice: possible role of adrenergic alpha2- and H3 histamine autoreceptors.

Neuropathic pain (NP) remains an untreatable disease due to the complex pathophysiology that involves the whole pain neuraxis including the forebrain. Sensory dysfunctions such as allodynia and hyperalgesia are only part of the symptoms associated with neuropathic pain that extend to memory and affectivity deficits. The development of multi-target molecules might be a promising therapeutic strategy against the symptoms associated with NP. 2-pentadecyl-2-oxazoline (PEA-OXA) is a plant-derived agent, which has shown effectiveness against chronic pain and associated neuropsychiatric disorders. The molecular mechanisms by which PEA-OXA exerts its effects are, however, only partially known. In the current study, we show that PEA-OXA, besides being an alpha2 adrenergic receptor antagonist, also acts as a modulator at histamine H3 receptors, and report data on its effects on sensory, affective and cognitive symptoms associated with the spared nerve injury (SNI) model of neuropathic pain in mice. Treatment for 14 days with PEA-OXA after the onset of the symptoms associated with neuropathic pain resulted in the following effects: (i) allodynia was decreased; (ii) affective/cognitive impairment associated with SNI (depression, spatial, and working memories) was counteracted; (iii) long-term potentiation in vivo in the lateral entorhinal cortex-dentate gyrus (perforant pathway, LPP) was ameliorated, (iv) hippocampal glutamate, GABA, histamine, norepinephrine and dopamine level alterations after peripheral nerve injury were reversed, (v) expression level of the TH positive neurons in the Locus Coeruleus were normalized. Thus, a 16-day treatment with PEA-OXA alleviates the sensory, emotional, cognitive, electrophysiological and neurochemical alterations associated with SNI-induced neuropathic pain.

T1AM-TAAR1 signalling protects against OGD-induced synaptic dysfunction in the entorhinal cortex.

Abnormalities in thyroid hormones (TH) availability and/or metabolism have been hypothesized to contribute to Alzheimer's disease (AD) and to be a risk factor for stroke. Recently, 3-iodothyronamine (T1AM), an endogenous amine putatively derived from TH metabolism, gained interest for its ability to promote learning and memory in the mouse. Moreover, T1AM has been demonstrated to rescue the ß-Amyloid dependent LTP impairment in the entorhinal cortex (EC), a brain area crucially involved in learning and memory and early affected during AD. In the present work, we have investigated the effect of T1AM on ischemia-induced EC synaptic dysfunction. In EC brain slices exposed to oxygen-glucose deprivation (OGD), we demonstrated that the acute perfusion of T1AM (5 µM) was capable of preventing ischemia-induced synaptic depression and that this protective effect was mediated by the trace amine-associated receptor 1 (TAAR1). Moreover, we demonstrated that activation of the BDNF-TrkB signalling is required for T1AM action during ischemia. The protective effect of T1AM was more evident when using EC slices from transgenic mutant human APP (mhAPP mice) that are more vulnerable to the effect of OGD. Our results confirm that the TH derivative T1AM can rescue synaptic function after transient ischemia, an effect that was also observed in a Aß-enriched environment.

The anticonvulsant zonisamide positively modulates recombinant and native glycine receptors at clinically relevant concentrations.

GABAA and glycine receptors mediate fast synaptic inhibitory neurotransmission. Despite studies showing that activation of cerebral glycine receptors could be a potential strategy in the treatment of epilepsy, few studies have assessed the effects of existing anticonvulsant therapies on recombinant or native glycine receptors. We, therefore, evaluated the actions of a series of anticonvulsants at recombinant human homo-oligomeric glycine receptor α1, α2 and α3 subtypes expressed in Xenopus oocytes using two-electrode voltage-clamp methods, and then assessed the most effective drug at native glycine receptors from entorhinal cortex neurons using whole-cell voltage-clamp recordings. Ganaxolone, tiagabine and zonisamide positively modulated glycine induced currents at recombinant homomeric glycine receptors. Of these, zonisamide was the most efficacious and exhibited an EC50 value ranging between 450 and 560 µM at α1, α2 and α3 subtypes. These values were not significantly different indicating a non-selective modulation of glycine receptors. Using a therapeutic concentration of zonisamide (100 µM), the potency of glycine was significantly shifted from 106 to 56 µM at α1, 185 to 112 µM at α2, and 245 to 91 µM at α3 receptors. Furthermore, zonisamide (100 µM) potentiated exogenous homomeric and heteromeric glycine mediated currents from layer II pyramidal cells of the lateral or medial entorhinal cortex. As therapeutic concentrations of zonisamide positively modulate recombinant and native glycine receptors, we propose that the anticonvulsant effects of zonisamide may, at least in part, be mediated via this action.

D-serine mitigates cell loss associated with temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is the most common type of drug-resistant epilepsy in adults, with an unknown etiology. A hallmark of TLE is the characteristic loss of layer 3 neurons in the medial entorhinal area (MEA) that underlies seizure development. One approach to intervention is preventing loss of these neurons through better understanding of underlying pathophysiological mechanisms. Here, we show that both neurons and glia together give rise to the pathology that is mitigated by the amino acid D-serine whose levels are potentially diminished under epileptic conditions. Focal administration of D-serine to the MEA attenuates neuronal loss in this region thereby preventing epileptogenesis in an animal model of TLE. Additionally, treatment with D-serine reduces astrocyte counts in the MEA, alters their reactive status, and attenuates proliferation and/or infiltration of microglia to the region thereby curtailing the deleterious consequences of neuroinflammation. Given the paucity of compounds that reduce hyperexcitability and neuron loss, have anti-inflammatory properties, and are well tolerated by the brain, D-serine, an endogenous amino acid, offers new hope as a therapeutic agent for refractory TLE.

Intramuscular Injection of BOTOX® Boosts Learning and Memory in Adult Mice in Association with Enriched Circulation of Platelets and Enhanced Density of Pyramidal Neurons in the Hippocampus.

BOTOX® is a therapeutic form of botulinum neurotoxin. It acts by blocking the release of acetylcholine (ACh) from the synaptic vesicles at the neuromuscular junctions, thereby inhibiting the muscle contraction. Notably, many neurological diseases have been characterized by movement disorders in association with abnormal levels of ACh. Thus, blockade of aberrant release of ACh appears to be a potential therapeutic strategy to mitigate many neurological deficits. BOTOX® has widely been used to manage a number of clinical complications like neuromuscular disorders, migraine and neuropathic pain. While the beneficial effects of BOTOX® against movement disorders have extensively been studied, its possible role in the outcome of cognitive function remains to be determined. Therefore, we investigated the effect of BOTOX® on learning and memory in experimental adult mice using behavioural paradigms such as open field task, Morris water maze and novel object recognition test in correlation with haematological parameters and histological assessments of the brain. Results revealed that a mild dose of BOTOX® treatment via an intramuscular route in adult animals improves learning and memory in association with increased number of circulating platelets and enhanced structural plasticity in the hippocampus. In the future, this minimally invasive treatment could be implemented to ameliorate different forms of dementia resulting from abnormal ageing and various neurocognitive disorders including Alzheimer's disease (AD).

Acute application of Centella asiatica extract enhanced AMPAR-mediated postsynaptic currents in rat entorhinal cortex.

Centella asiatica is notable for its wide range of biological activities beneficial to human health, particularly its cognitive enhancement and neuroprotective effects. The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors are ionotropic glutamate receptors mediating fast excitatory neurotransmission essential in long-term potentiation widely thought to be the cellular mechanism of learning and memory. The method of whole-cell patch-clamp was used to study the effect of the acute application of Centella asiatica extract on the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated spontaneous excitatory postsynaptic currents in the entorhinal cortex of rat brain slices. The respective low dose of test compounds significantly increased the amplitude of spontaneous excitatory postsynaptic currents while having no significant effects on the frequency. The findings suggested that Centella asiatica extract increased the response of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors at the postsynaptic level, revealing the potential role of Centella asiatica in modulating the glutamatergic responses in the entorhinal cortex of rat brain slices to produce cognitive enhancement effects.

Activity- and pH-dependent adenosine shifts at the end of a focal seizure in the entorhinal cortex.

Adenosine (ADO) is an endogenous modulator of neuronal excitability, with anticonvulsant and neuroprotective effects. It has been proposed that the activity-dependent release of ADO promoted by the extracellular acidification occurring during seizures contributes to seizure termination. To verify this hypothesis, we recorded field potentials, pH and ADO changes measured with enzymatic biosensors during acute focal seizures in the medial entorhinal cortex (mEC) of the isolated guinea-pig brain maintained in vitro. The effect of ADO on seizure-like events (SLEs) induced by GABAa receptor antagonism with bicuculline methiodide (BMI; 50 µM) was assessed by arterial applications of 1 mM ADO. ADO either reduced or prevented epileptiform activity. The A1 receptor antagonist DPCPX (100-500 µM) prolonged BMI-induced seizures and was able to precipitate SLEs in the absence of proconvulsant. Simultaneous recordings of brain activity, extracellular ADO and pH shifts demonstrated that ADO decreases at the onset and progressively rises toward the end of SLEs induced by either BMI or 4-aminopyridine (4AP; 50 µM), reaching maximal values 1-5 min after SLE termination. ADO changes were preceded by a SLE-dependent extracellular acid shift. Both pH acidification and ADO changes were abolished by 22 mM HEPES in the arterial perfusate. In these conditions, SLE duration was prolonged. Our data confirm that ADO plays a role in regulating brain excitability. Its increase depends on seizure-induced acid pH shift and it is maximal after the end of the SLE. These findings strongly suggest that ADO contributes to termination of focal seizures and to the establishment of the postictal depression.

Cyclosomatostatin-induced catalepsy in aged rats: Specific change of brain c-Fos protein expression in the lateral entorhinal cortex.

Aging represents the largest risk factor for developing Parkinson's disease (PD); another salient feature of this disorder is a decreased brain levels of somatostatin. Recently, in aged Wistar rats, we simulated the central somatostatinergic deficiency by intracerebroventricular injections of a somatostatin antagonist, cyclosomatostatin (cSST). The treated animals displayed catalepsy, a state that resembles the extrapyramidal signs of Parkinson's disease; young animals were insensitive to cSST. The neuroanatomical substrates responsible for the increased cataleptogenic activity of cSST in aged animals, are currently unknown. To study this issue, we assessed the cSST effect on brain c-Fos-protein expression in aged and young rats; thirty three brain regions were examined. cSST was employed at the dose cataleptogenic for aged animals and non-cataleptogenic for young ones. c-Fos expression patterns in the 'cataleptic' and 'non-cataleptic' animals were very similar, with the only distinction being a decrease in the c-Fos expression in the aged lateral entorhinal cortex (LEntCx). This decrease was not observed when the cSST-induced cataleptic response was inhibited by administration of diphenhydramine and nicotine. Thus, the development of catalepsy in the aged Wistar rats appeared to be associated with a hypoactivation of the LEntCx; possibly, there exists a mechanistic link between the LEntCx hypoactivation and increased susceptibility of aged rats to catalepsy. Apparently, these findings may provide novel insight into the link between mechanisms of parkinsonian motor disorders and aging.

KCC2 antagonism and gabaergic synchronization in the entorhinal cortex in the absence of ionotropic glutamatergic receptor signalling.

γ-Aminobutyric acid (GABA), which is released by interneurons, plays an active role in generating interictal epileptiform spikes during blockade of ionotropic glutamatergic signalling, but it remains unclear whether and how the K+-Cl- cotransporter 2 (KCC2) influences these paroxysmal events. Therefore, we employed tetrode recordings in the in vitro rat entorhinal cortex (EC) to analyze the effects of the KCC2 antagonist VU0463271 on 4-aminopyridine (4AP)-induced interictal spikes that were pharmacologically isolated by applying ionotropic glutamatergic receptor antagonists. After the addition of VU0463271, these interictal spikes continued to occur at similar rates as in control (i.e., during application of 4AP with ionotropic glutamatergic receptor antagonists) but were smaller and shorter. Despite the absence of ionotropic glutamatergic receptor signalling, both interneurons and principal cells increased their firing during interictal spikes. Moreover, we found that KCC2 antagonism increased interneuron firing but decreased principal cell firing during the interictal spike rising phase; in contrast, during the falling phase, interneuron firing decreased in the presence of VU0463271 while no change was observed in principal cell firing. Overall, our results show that KCC2 antagonism enhances interneuron excitability at the onset of interictal spikes generated by the EC neuronal networks during blockade of ionotropic glutamatergic transmission but disrupts later neuronal recruitment.

Cholinergic Switch between Two Types of Slow Waves in Cerebral Cortex.

Sleep slow waves are known to participate in memory consolidation, yet slow waves occurring under anesthesia present no positive effects on memory. Here, we shed light onto this paradox, based on a combination of extracellular recordings in vivo, in vitro, and computational models. We find two types of slow waves, based on analyzing the temporal patterns of successive slow-wave events. The first type is consistently observed in natural slow-wave sleep, while the second is shown to be ubiquitous under anesthesia. Network models of spiking neurons predict that the two slow wave types emerge due to a different gain on inhibitory versus excitatory cells and that different levels of spike-frequency adaptation in excitatory cells can account for dynamical distinctions between the two types. This prediction was tested in vitro by varying adaptation strength using an agonist of acetylcholine receptors, which demonstrated a neuromodulatory switch between the two types of slow waves. Finally, we show that the first type of slow-wave dynamics is more sensitive to external stimuli, which can explain how slow waves in sleep and anesthesia differentially affect memory consolidation, as well as provide a link between slow-wave dynamics and memory diseases.

Decreased medial entorhinal cortical thickness in olanzapine exposed female rats is not ameliorated by exercise.

Aerobic exercise has been associated with hippocampal plasticity, both in healthy adults and in psychosis patients, but its impact on cortical regions remains unclear. The entorhinal cortex serves as a critical gateway for the hippocampus, and recent studies suggest that this region may also be impacted following an exercise regime. In order to investigate the effects of antipsychotic medications and exercise on the entorhinal cortex, female rats were chronically administered either olanzapine or vehicle and were either sedentary or had access to a running wheel for 9 weeks. Olanzapine-treated rats had decreased medial entorhinal cortical thickness compared to vehicle-treated rats. A statistically significant interaction was observed for layer II of the entorhinal cortex, with exercising rats having significantly greater thickness compared to sedentary rats in the vehicle group, but not the olanzapine group. Greater total entorhinal and lateral entorhinal cortical thickness was associated with greater average activity. In exercising rats, decreasing glucose intolerance was associated with larger total entorhinal and layer II cortical thickness. Lower fasting insulin levels were associated with greater total entorhinal, lateral entorhinal, and layer II cortical thickness. The relationship between increased activity and greater entorhinal cortical thickness was mediated by reduced fasting insulin, indicating that regulation of metabolic risk factors may contribute to impact of aerobic exercise on the entorhinal cortex. Aerobic exercise may be helpful in counteracting metabolic side effects of antipsychotic medications and managing these side effects may be key to promoting entorhinal cortical plasticity in patients treated with second-generation antipsychotic drugs.

Regional differences in Alzheimer's disease pathology confound behavioural rescue after amyloid-ß attenuation.

Failure of Alzheimer's disease clinical trials to improve or stabilize cognition has led to the need for a better understanding of the driving forces behind cognitive decline in the presence of active disease processes. To dissect contributions of individual pathologies to cognitive function, we used the TgF344-AD rat model, which recapitulates the salient hallmarks of Alzheimer's disease pathology observed in patient populations (amyloid, tau inclusions, frank neuronal loss, and cognitive deficits). scyllo-Inositol treatment attenuated amyloid-ß peptide in disease-bearing TgF344-AD rats, which rescued pattern separation in the novel object recognition task and executive function in the reversal learning phase of the Barnes maze. Interestingly, neither activities of daily living in the burrowing task nor spatial memory in the Barnes maze were rescued by attenuating amyloid-ß peptide. To understand the pathological correlates leading to behavioural rescue, we examined the neuropathology and in vivo electrophysiological signature of the hippocampus. Amyloid-ß peptide attenuation reduced hippocampal tau pathology and rescued adult hippocampal neurogenesis and neuronal function, via improvements in cross-frequency coupling between theta and gamma bands. To investigate mechanisms underlying the persistence of spatial memory deficits, we next examined neuropathology in the entorhinal cortex, a region whose input to the hippocampus is required for spatial memory. Reduction of amyloid-ß peptide in the entorhinal cortex had no effect on entorhinal tau pathology or entorhinal-hippocampal neuronal network dysfunction, as measured by an impairment in hippocampal response to entorhinal stimulation. Thus, rescue or not of cognitive function is dependent on regional differences of amyloid-ß, tau and neuronal network dysfunction, demonstrating the importance of staging disease in patients prior to enrolment in clinical trials. These results further emphasize the need for combination therapeutic approaches across disease progression.

Exogenous 3-Iodothyronamine Rescues the Entorhinal Cortex from ß-Amyloid Toxicity.

Background: A novel form of thyroid hormone (TH) signaling is represented by 3-iodothyronamine (T1AM), an endogenous TH derivative that interacts with specific molecular targets, including trace amine-associated receptor 1 (TAAR1), and induces pro-learning and anti-amnestic effects in mice. Dysregulation of TH signaling has long been hypothesized to play a role in Alzheimer's disease (AD). In the present investigation, we explored the neuroprotective role of T1AM in beta amyloid (Aß)-induced synaptic and behavioral impairment, focusing on the entorhinal cortex (EC), an area that is affected early by AD pathology. Methods: Field potentials were evoked in EC layer II, and long-term potentiation (LTP) was elicited by high frequency stimulation (HFS). T1AM (5 µM) and/or Aß(1-42) (200 nM), were administered for 10 minutes, starting 5 minutes before HFS. Selective TAAR1 agonist RO5166017 (250 nM) and TAAR1 antagonist EPPTB (5 nM) were also used. The electrophysiological experiments were repeated in EC-slices taken from a mouse model of AD (mutant human amyloid precursor protein [mhAPP], J20 line). We also assessed the in vivo effects of T1AM on EC-dependent associative memory deficits, which were detected in mhAPP mice by behavioral evaluations based on the novel-object recognition paradigm. TAAR1 expression was determined by Western blot, whereas T1AM and its metabolite 3-iodothyroacetic acid (TA1) were assayed by high-performance liquid chromatography coupled to mass spectrometry. Results: We demonstrate the presence of endogenous T1AM and TAAR1 in the EC of wild-type and mhAPP mice. Exposure to Aß(1-42) inhibited LTP, and T1AM perfusion (at a concentration of 5 µM, leading to an actual concentration in the perfusion buffer ranging from 44 to 298 nM) restored it, whereas equimolar amounts of 3,5,3'-triiodo-L-thyronine (T3) and TA1 were ineffective. The response to T1AM was abolished by the TAAR1 antagonist EPPTB, whereas it was mimicked by the TAAR1 agonist RO5166017. In the EC of APPJ20 mice, LTP could not be elicited, but it was rescued by T1AM. The intra-cerebro-ventricular administration of T1AM (0.89 µg/kg) also restored recognition memory that was impaired in mhAPP mice. Conclusions: Our results suggest that T1AM and TAAR1 are part of an endogenous system that can be modulated to prevent synaptic and behavioral deficits associated with Aß-related toxicity.

The effects of developmental alcohol exposure on the neurobiology of spatial processing.

The consumption of alcohol during gestation is detrimental to the developing central nervous system. One functional outcome of this exposure is impaired spatial processing, defined as sensing and integrating information pertaining to spatial navigation and spatial memory. The hippocampus, entorhinal cortex, and anterior thalamus are brain regions implicated in spatial processing and are highly susceptible to the effects of developmental alcohol exposure. Some of the observed effects of alcohol on spatial processing may be attributed to changes at the synaptic to circuit level. In this review, we first describe the impact of developmental alcohol exposure on spatial behavior followed by a summary of the development of brain areas involved in spatial processing. We then provide an examination of the consequences of prenatal and early postnatal alcohol exposure in rodents on hippocampal, anterior thalamus, and entorhinal cortex-dependent spatial processing from the cellular to behavioral level. We conclude by highlighting several unanswered questions which may provide a framework for future investigation.

Antidepressants upregulate c-Fos expression in the lateral entorhinal cortex and hippocampal dorsal subiculum: Study in rats.

Neural circuits involved in the development of depression are currently poorly understood. To provide insight into this issue, we evaluated the influence of seven clinically effective antidepressants on neuronal activity in thirty rat brain areas. Drugs belonging to all major groups of antidepressants (imipramine, reboxetine, fluoxetine, bupropion, mirtazapine, agomelatine, and phenelzine) were examined; since antidepressants typically require weeks of continued administration before they achieve a therapeutic effect, we administered these drugs for 21 days. The experiments were conducted with male Wistar rats. To identify the neuroanatomical targets for antidepressants, the alterations of c-Fos expression in different brain areas were measured using ELISA assay. The drugs were examined at doses sufficient to produce behavioral effect in the rat forced swim test (FST). All the drugs at the behaviorally relevant doses activated two brain areas, the lateral entorhinal cortex and dorsal subiculum of the hippocampus; none of the drugs affected the c-Fos expression in the medial orbital, prelimbic and infralimbic cortex, caudate putamen, nucleus accumbens core, bed nucleus of stria terminalis, hipothalamic paraventricular nucleus, medial amygdaloid nucleus, lateral habenula, substantia nigra pars compacta and pars reticulata, ventral tegmental area, hippocampal ventral subiculum, dorsal and ventral periaqueductal gray matters, and medial entorhinal cortex. These findings suggest that the stimulation of the lateral entorhinal cortex and hippocampal dorsal subiculum play a role in therapeutic effects of antidepressants.

KCC2 antagonism increases neuronal network excitability but disrupts ictogenesis in vitro.

The potassium-chloride cotransporter 2 (KCC2) plays a role in epileptiform synchronization, but it remains unclear how it influences such a process. Here, we used tetrode recordings in the in vitro rat entorhinal cortex (EC) to analyze the effects of the KCC2 antagonist VU0463271 on 4-aminopyridine (4AP)-induced ictal and interictal activity. During 4AP application, ictal events were associated with significant increases in interneurons and principal cells activities. VU0463271 application transformed ictal discharges to shorter ictal-like events that were not accompanied by significant increases in interneuron or principal cell firing. Interictal events persisted during VU0463271 application at an accelerated frequency of occurrence with significant increases in interneuron and principal cell activity. Further analysis revealed that interneuron and principal cell firing rate during 4AP-induced interictal events were increased after VU0463271 application without changes in synchronicity. Overall, our results demonstrate that in the EC, KCC2 antagonism enhances both interneuron and principal cell excitability, while paradoxically decreasing the ability of neuronal networks to generate structured ictal events.NEW & NOTEWORTHY We are the first to use tetrode recordings in the entorhinal cortex to demonstrate that antagonizing potassium-chloride cotransporter 2 (KCC2) function abolishes ictal discharges and the associated, dynamic changes in single-unit firing in the in vitro 4-aminopyrine model of epileptiform synchronization. Interictal discharges were, however, shorter and more frequent during KCC2 antagonism, while the associated single-unit activity increased, suggesting augmented neuronal excitability. Our findings highlight the complex role of KCC2 in disease pathology.