The Molecular Basis for the Calcium-Dependent Slow Afterhyperpolarization in CA1 Hippocampal Pyramidal Neurons

Neuronal signal transmission depends on the frequency, pattern, and timing of spike output, each of which are shaped by spike afterhyperpolarizations (AHPs). There are classically three post-spike AHPs of increasing duration categorized as fast, medium and slow AHPs that hyperpolarize a cell over a range of 10 ms to 30 s. Intensive early work on CA1 hippocampal pyramidal cells revealed that all three AHPs incorporate activation of calcium-gated potassium channels. The ionic basis for a fAHP was rapidly attributed to the actions of big conductance (BK) and the mAHP to small conductance (SK) or Kv7 potassium channels. In stark contrast, the ionic basis for a prominent slow AHP of up to 30 s duration remained an enigma for over 30 years. Recent advances in pharmacological, molecular, and imaging tools have uncovered the expression of a calcium-gated intermediate conductance potassium channel (IK, KCa3.1) in central neurons that proves to contribute to the slow AHP in CA1 hippocampal pyramidal cells. Together the data show that the sAHP arises in part from a core tripartite complex between Cav1.3 (L-type) calcium channels, ryanodine receptors, and IK channels at endoplasmic reticulum-plasma membrane junctions. Work on the sAHP in CA1 pyramidal neurons has again quickened pace, with identified contributions by both IK channels and the Na-K pump providing answers to several mysteries in the pharmacological properties of the sAHP.

Subchronic high dose of oral monosodium glutamate causes structural and functional deficits of rat hippocampus

The toxicity of monosodium glutamate (MSG) at high concentration has become a controversial issue because of its inconsistent results in human and animal studies. This study aims to investigate the effects of subchronic high doses oral administration of MSG on the spatial memory and the estimated total number of the hippocampal pyramidal cells. This study involved twenty-eight male Wistar rats which were divided into control group and 3 intervention groups (1.0 mg/g body weight, 2.0 mg/g body weight, and 4.0 mg/g body weight) of MSG for 30 days. The estimated number of hippocampal pyramidal cells in the Cornu Ammonis (CA) region including CA1 and CA2-CA3 regions and the data of spatial memory were analyzed using ANOVA test. This study implemented stereological procedures and the precision was evaluated using the formula. The dose of 4 mg/g body weight MSG caused a significant decrease (p = 0.004) in the estimated number of pyramidal cells in CA1, but not in the CA2-CA3 of hippocampus (p = 0.173). The CA1 region were more vulnerable to glutamate excitotoxicity than those in the CA2-CA3 region. The present study has provided novel quantitative data that subchronic high dose of MSG caused deleterious effects on the hippocampal CA1 pyramidal cells and memory consolidation.

Do hippocampal pyramidal cells respond to non-spatial stimuli?

There are currently a number of theories of rodent hippocampal function. They fall into two major groups which differ in the role they impute to space in hippocampal information processing. On the one hand, the cognitive map theory sees space as crucial and central, with other types of non-spatial information embedded in a primary spatial framework. On the other hand, most other theories see the function of the hippocampal formation as broader, treating all types of information as equivalent and concentrating on the processes carried out irrespective of the specific material being represented, stored and manipulated. One crucial difference therefore is the extent to which theories see hippocampal pyramidal cells as representing non-spatial information independently of a spatial framework. Studies have reported the existence of single hippocampal unit responses to non-spatial stimuli, both to simple sensory inputs as well as to more complex stimuli such as objects, conspecifics, rewards and time, and these findings been interpreted as evidence in favor of a broader hippocampal function. Alternatively, these non-spatial responses might actually be feature-in-place signals where the spatial nature of the response has been masked by the fact that the objects or features were only presented in one location or one spatial context. In this paper, we argue that when tested in multiple locations, the hippocampal response to non-spatial stimuli is almost invariably dependent on the animal's location. Looked at collectively, the data provide strong support for the cognitive map theory.

Prevention of Brain Hypoperfusion-Induced Neurodegeneration in Rat’s Hippocampus by Black Cumin Fixed Oil Treatment

Introduction: The oil extract of black cumin seeds Nigella sativa (NSO) demonstrated considerable preservation of spatial cognitive functions in rats subjected to chronic brain hypoperfusion (CBH). The hippocampal CA1 region pyramidal cells are the earliest neurons suffering neurodegeneration following CBH. Objective: The current study was devoted to assess the protective effects of Nigella sativa (NSO) treatment on CA1 hippocampal pyramidal cells of rats subjected to chronic brain hypoperfusion (CBH) that was achieved through permanent two vessel occlusion (2VO) procedure. Methods: Twenty four rats were equally divided into three groups; sham control, untreated 2VO and NSO treated group (2VO with daily oral NSO treatment. After the 10th postoperative week coronal sections of the hippocampus were collected for histopathological and electron microscopical examinations. Results: The number of viable pyramidal cells within CA1 hippocampal region in sham control and NSO treated groups was significantly higher than that of untreated 2VO group, while the difference was not significant when comparing the viable pyramidal cells number of sham control with NSO treated groups. Furthermore, 2VO group showed marked intracellular ultrastructural distortions that were less pronounced in NSO treated group. Conclusion: NSO displayed a robust potential to protect hippocampal pyramidal cells from CBH induced neurodegeneration putting forward its prospective neuroprotective activity against age related cognitive decline of Alzheimer’s disease and vascular dementia.

Activating mGlu3 metabotropic glutamate receptors rescues schizophrenia-like cognitive deficits through metaplastic adaptations within the hippocampus

BackgroundPolymorphisms in GRM3, the gene encoding the mGlu3 metabotropic glutamate receptor, are associated with impaired cognition and neuropsychiatric disorders such as schizophrenia. Limited availability of selective genetic and molecular tools has hindered progress in developing a clear understanding of the mechanisms through which mGlu3 receptors regulate synaptic plasticity and cognition.MethodsWe examined associative learning in mice with trace fear conditioning, a hippocampal-dependent learning task disrupted in patients with schizophrenia. Underlying cellular mechanisms were assessed using ex vivo hippocampal slice preparations with selective pharmacological tools and selective genetic deletion of mGlu3 receptor expression in specific neuronal subpopulations.ResultsmGlu3 receptor activation enhanced trace fear conditioning and reversed deficits induced by subchronic phencyclidine. Mechanistic studies revealed that mGlu3 receptor activation induced metaplastic changes, biasing afferent stimulation to induce long-term potentiation through a mGlu5 receptor-dependent, endocannabinoid-mediated, disinhibitory mechanism. Selective genetic deletion of either mGlu3 or mGlu5 from hippocampal pyramidal cells eliminated effects of mGlu3 activation, revealing a novel mechanism by which mGlu3 and mGlu5 interact to enhance cognitive function.ConclusionsThese data demonstrate that activation of mGlu3 receptors in hippocampal pyramidal cells enhances hippocampal-dependent cognition in control and impaired mice by inducing a novel form of metaplasticity to regulate circuit function – providing a clear mechanism through which genetic variation in GRM3 can contribute to cognitive deficits. Developing approaches to positively modulate mGlu3 receptor function represents an encouraging new avenue for treating cognitive disruption in schizophrenia and other psychiatric diseases.

The dendritic spatial code: branch-specific place tuning and its experience-dependent decoupling

Dendrites of pyramidal neurons integrate different sensory inputs, and non-linear dendritic computations drive feature selective tuning and plasticity. Yet little is known about how dendrites themselves represent the environment, the degree to which they are coupled to their soma, and how that coupling is sculpted with experience. In order to answer these questions, we developed a novel preparation in which we image soma and connected dendrites in a single plane across days using in vivo two-photon microscopy. Using this preparation, we monitored spatially tuned activity in area CA3 of the hippocampus in head-fixed mice running on a linear track. We identified “place dendrites”, which can stably and precisely represent both familiar and novel spatial environments. Dendrites could display place tuning independent of their connected soma and even their sister dendritic branches, the first evidence for branch-specific tuning in the hippocampus. In a familiar environment, spatially tuned somata were more decoupled from their dendrites as compared to non-tuned somata. This relationship was absent in a novel environment, suggesting an experience dependent selective gating of dendritic spatial inputs. We then built a data-driven multicompartment computational model that could capture the experimentally observed correlations. Our model predicts that place cells exhibiting branch-specific tuning have more flexible place fields, while neurons with homogenous or co-tuned dendritic branches have higher place field stability. These findings demonstrate that spatial representation is organized in a branch-specific manner within dendrites of hippocampal pyramidal cells. Further, spatial inputs from dendrites to soma are selectively and dynamically gated in an experience-dependent manner, endowing both flexibility and stability to the cognitive map of space.One sentence summaryHippocampal pyramidal cells show branch-specific tuning for different place fields, and their coupling to their soma changes with experience of an environment.

Evidence for Decreased Nucleolar PARP-1 as an Early Marker of Cognitive Impairment

Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear protein that regulates gene expression through poly(ADP)-ribosylation, resulting in the loosening of chromatin structure. PARP-1 enzymatic activity has been shown to be necessary for the expression of several genes required for memory formation and consolidation. Previously, we showed that nucleolar PARP-1 is significantly decreased in hippocampal pyramidal cells in Alzheimer’s disease (AD). We proposed that the displacement of PARP-1 from the nucleolus results in downregulation of new rRNA expression and ribosome biogenesis, leading to cognitive impairment. To further investigate the relationship between nucleolar PARP-1 and memory impairment, we examined PARP-1 expression in the hippocampi of individuals with mild cognitive impairment (MCI) compared to control and AD cases. We used immunohistochemical techniques to examine the nucleolar distribution of PARP-1 in the Cornu Ammonis (CA region) of the hippocampus. PARP-1 positive cells were then scored for the presence or absence of PARP-1 in the nucleolus. We found a significant decrease of PARP-1 staining in the nucleolar compartment of hippocampal pyramidal cells in MCI compared with Control and AD. When the four CA (CA1-4) regions were considered separately, only the CA1 region showed significant differences in nucleolar PARP-1 with Control > AD > MCI cases. Categorization of nucleolar PARP-1 into “distinct” and “diffuse” groups suggest that most of the changes occur within the distinct group. In addition, measurements of the nucleolar diameter of nucleolar PARP-1 positive cells in CA2 and CA4 showed Control > MCI. Thus, MCI cases had a lower percentage of PARP-1 nucleolar positive cells in CA1 and smaller nucleolar diameters in CA2 and CA4, compared to Control. Our data suggest that disruption of nucleolar form and function is an early and important step in the progression of cognitive impairment.