CA1 Pyramidal Cells Research Articles

Developmental, cellular, and behavioral phenotypes in a mouse model of congenital hypoplasia of the dentate gyrus.

In the hippocampus, a widely accepted model posits that the dentate gyrus improves learning and memory by enhancing discrimination between inputs. To test this model, we studied conditional knockout mice in which the vast majority of dentate granule cells (DGCs) fail to develop - including nearly all DGCs in the dorsal hippocampus - secondary to eliminating Wntless (Wls) in a subset of cortical progenitors with Gfap-Cre. Other cells in the Wlsfl/-;Gfap-Cre hippocampus were minimally affected, as determined by single nucleus RNA sequencing. CA3 pyramidal cells, the targets of DGC-derived mossy fibers, exhibited normal morphologies with a small reduction in the numbers of synaptic spines. Wlsfl/-;Gfap-Cre mice have a modest performance decrement in several complex spatial tasks, including active place avoidance. They were also modestly impaired in one simpler spatial task, finding a visible platform in the Morris water maze. These experiments support a role for DGCs in enhancing spatial learning and memory.

Age-Dependent Shift of AMPA Receptors From Synapses to Intracellular Compartments in Alzheimer's Disease: Immunocytochemical Analysis of the CA1 Hippocampal Region in APP/PS1 Transgenic Mouse Model.

Synapse loss occurs early in Alzheimer’s disease (AD) patients and animal models. Alterations at synaptic level are a major morphological correlate of the memory deficits and related symptoms of AD. Given the predominant roles of synaptic AMPA receptors (AMPARs) in excitatory synaptic transmission in the brain, changes in their dynamic regulation are also implicated in the pathophysiology of AD. Here, we used immunolocalization techniques to analyze the expression and subcellular distribution of AMPARs in the hippocampal region of APP/PS1 mouse model of AD. Immunoblots and histoblots revealed that the total amount of AMPARs and their regional expression pattern in the hippocampus was similar in APP/PS1 mice and in age-matched wild type mice. At the ultrastructural level, two synapse populations were examined using SDS-digested freeze-fracture replica labeling in the stratum radiatum in mice: (i) on spines of CA1 pyramidal cells; and (ii) on randomly found dendritic shafts of CA1 interneurons. While 1- and 6-months-old APP/PS1 mice exhibited no change, we observed a significant reduction at 12 months in AMPAR density at synapses in both pyramidal cells and interneurons, compared to wild-type. This reduction of AMPARs in dendritic spines was accompanied by a significant increase in AMPAR subunit proteins identified in intracellular compartments. Our data demonstrate an age-dependent reduction of synaptic AMPARs in APP/PS1 mice, which may contribute to impaired learning and memory at later stages of AD.

Contextual Fear Memory Retrieval Is Vulnerable to Hippocampal Noise.

Memory retrieval depends on reactivation of memory engram cells. Inadvertent activation of these cells is expected to cause memory-retrieval failure, but little is known about how noisy activity of memory-irrelevant neurons impacts mnemonic processes. Here, we report that optogenetic nonselective activation of only tens of hippocampal CA1 cells (∼0.01% of the total cells in the CA1 pyramidal cell layer) impairs contextual fear memory recall. Memory recall failure was associated with altered neuronal reactivation in the basolateral amygdala. These results indicate that hippocampal memory retrieval requires strictly regulated activation of a specific neuron ensemble and is easily disrupted by the introduction of noisy CA1 activity, suggesting that reactivating memory engram cells as well as silencing memory-irrelevant neurons are both crucial for memory retrieval.

Bidirectional regulation of distinct memory domains by α5-subunit-containing GABAA receptors in CA1 pyramidal neurons.

Reduction in the expression or function of α5-subunit-containing GABAA receptors (α5GABAARs) leads to improvement in several hippocampus-dependent memory domains. However, studies thus far mostly lack anatomical specificity in terms of neuronal circuits and populations. We demonstrate that mice with a selective knockdown of α5GABAARs in CA1 pyramidal neurons (α5CA1KO mice) show improved spatial and trace fear-conditioning memory. Unexpectedly, α5CA1KO mice were comparable to controls in contextual fear-conditioning but showed an impairment in context discrimination, suggesting fine-tuning of activity in CA1 pyramidal cell dendrites through α5-mediated inhibition might be necessary for distinguishing highly similar contexts.

VEGF-D Downregulation in CA1 Pyramidal Neurons Exerts Asymmetric Changes of Dendritic Morphology without Correlated Electrophysiological Alterations

The morphology of dendritic arbors determines the location, strength and interaction of synaptic inputs. It is therefore important to understand the factors regulating dendritic arborization both during development and in situations of physiological or pathological plasticity. We have recently shown that VEGF-D (Vascular Endothelial Growth Factor D) is required to maintain length and complexity of basal dendrites in mouse hippocampal pyramidal cells. Lack of VEGF-D resulted in long-term memory deficits, suggesting a link between dendritic morphology and cognitive function. Here, we compared the effect of VEGF-D expression on basal versus apical dendrites of CA1 pyramidal cells, as well as its importance for synaptic processing of network oscillations. We report opposing, layer-specific effects of VEGF-D knockdown which resulted in shrinkage of basal and increased complexity of apical dendrites. Synaptic potentials and layer-specific voltage gradients during network oscillations remained, however, unaltered. These findings reveal a high spatial selectivity of VEGF-D effects at the sub-cellular level, and strong homeostatic mechanisms which keep spatially segregated synaptic inputs in a balance.

Preparing Acute Brain Slices from the Dorsal Pole of the Hippocampus from Adult Rodents.

Whole-cell patch-clamp recordings from acute rodent brain slices are a mainstay of modern neurophysiological research, allowing precise measurement of cellular and synaptic properties. Nevertheless, there is an ever increasing need to perform correlated analyses between different experimental modes in addition to slice electrophysiology, for example: immunohistochemistry, molecular biology, in vivo imaging or electrophysiological recording; to answer evermore complex questions of brain function. However, making meaningful conclusions from these various experimental approaches is not straightforward, as even within relatively well described brain structures, a high degree of sub-regional variation of cellular function exists. Nowhere is this better exemplified than in the CA1 of the hippocampus, which has well-defined dorso-ventral properties, based on cellular and molecular properties. Nevertheless, many published studies examine protein expression patterns or behaviorally correlated in vivo activity in the dorsal extent of the hippocampus; and explain findings mechanistically with cellular electrophysiology from the ventro-medial region. This is further confounded by the fact that many acute slice electrophysiological experiments are performed in juvenile animals, when other experimental modes are performed in more mature animals. To address these issues, this method incorporates transcardial perfusion of mature (>60 day old rodents) with artificial cerebrospinal fluid followed by preparation of modified coronal slices including the septal pole of the dorsal hippocampus to record from CA1 pyramidal cells. This process leads to the generation of healthy acute slices of dorsal hippocampus allowing for slice-based cellular electrophysiological interrogation matched to other measures.

A Computational Model of the Cholinergic Modulation of CA1 Pyramidal Cell Activity.

Dysfunction in cholinergic modulation has been linked to a variety of cognitive disorders including Alzheimer's disease. The important role of this neurotransmitter has been explored in a variety of experiments, yet many questions remain unanswered about the contribution of cholinergic modulation to healthy hippocampal function. To address this question, we have developed a model of CA1 pyramidal neuron that takes into consideration muscarinic receptor activation in response to changes in extracellular concentration of acetylcholine and its effects on cellular excitability and downstream intracellular calcium dynamics. This model incorporates a variety of molecular agents to accurately simulate several processes heretofore ignored in computational modeling of CA1 pyramidal neurons. These processes include the inhibition of ionic channels by phospholipid depletion along with the release of calcium from intracellular stores (i.e., the endoplasmic reticulum). This paper describes the model and the methods used to calibrate its behavior to match experimental results. The result of this work is a compartmental model with calibrated mechanisms for simulating the intracellular calcium dynamics of CA1 pyramidal cells with a focus on those related to release from calcium stores in the endoplasmic reticulum. From this model we also make various predictions for how the inhibitory and excitatory responses to cholinergic modulation vary with agonist concentration. This model expands the capabilities of CA1 pyramidal cell models through the explicit modeling of molecular interactions involved in healthy cognitive function and disease. Through this expanded model we come closer to simulating these diseases and gaining the knowledge required to develop novel treatments.

Interneuron-specific plasticity at parvalbumin and somatostatin inhibitory synapses onto CA1 pyramidal neurons shapes hippocampal output

The formation and maintenance of spatial representations within hippocampal cell assemblies is strongly dictated by patterns of inhibition from diverse interneuron populations. Although it is known that inhibitory synaptic strength is malleable, induction of long-term plasticity at distinct inhibitory synapses and its regulation of hippocampal network activity is not well understood. Here, we show that inhibitory synapses from parvalbumin and somatostatin expressing interneurons undergo long-term depression and potentiation respectively (PV-iLTD and SST-iLTP) during physiological activity patterns. Both forms of plasticity rely on T-type calcium channel activation to confer synapse specificity but otherwise employ distinct mechanisms. Since parvalbumin and somatostatin interneurons preferentially target perisomatic and distal dendritic regions respectively of CA1 pyramidal cells, PV-iLTD and SST-iLTP coordinate a reprioritisation of excitatory inputs from entorhinal cortex and CA3. Furthermore, circuit-level modelling reveals that PV-iLTD and SST-iLTP cooperate to stabilise place cells while facilitating representation of multiple unique environments within the hippocampal network.

Limiting RyR2 Open Time Prevents Alzheimer’s Disease-Related Neuronal Hyperactivity and Memory Loss but Not β-Amyloid Accumulation

SUMMARYNeuronal hyperactivity is an early primary dysfunction in Alzheimer’s disease (AD) in humans and animal models, but effective neuronal hyperactivity-directed anti-AD therapeutic agents are lacking. Here we define a previously unknown mode of ryanodine receptor 2 (RyR2) control of neuronal hyperactivity and AD progression. We show that a single RyR2 point mutation, E4872Q, which reduces RyR2 open time, prevents hyperexcitability, hyperactivity, memory impairment, neuronal cell death, and dendritic spine loss in a severe early-onset AD mouse model (5xFAD). The RyR2-E4872Q mutation upregulates hippocampal CA1-pyramidal cell A-type K+ current, a well-known neuronal excitability control that is downregulated in AD. Pharmacologically limiting RyR2 open time with the R-carvedilol enantiomer (but not racemic carvedilol) prevents and rescues neuronal hyperactivity, memory impairment, and neuron loss even in late stages of AD. These AD-related deficits are prevented even with continued β-amyloid accumulation. Thus, limiting RyR2 open time may be a hyperactivity-directed, non-β-amyloid-targeted anti-AD strategy.

Pycnogenol® Supplementation Attenuates Memory Deficits and Protects Hippocampal CA1 Pyramidal Neurons via Antioxidative Role in a Gerbil Model of Transient Forebrain Ischemia.

Pycnogenol® (an extract of the bark of French maritime pine tree) is used for dietary supplement and known to have excellent antioxidative efficacy. However, there are few reports on neuroprotective effect of Pycnogenol® supplementation and its mechanisms against ischemic injury following transient forebrain ischemia (TFI) in gerbils. Now, we examined neuroprotective effect and its mechanisms of Pycnogenol® in the gerbils with 5-min TFI, which evokes a significant death (loss) of pyramidal cells located in the cornu ammonis (CA1) region of gerbil hippocampus from 4–5 days post-TFI. Gerbils were pretreated with 30, 40, and 50 mg/kg of Pycnogenol® once a day for 7 days before TFI surgery. Treatment with 50 mg/kg, not 30 or 40 mg/kg, of Pycnogenol® potently protected learning and memory, as well as CA1 pyramidal cells, from ischemic injury. Treatment with 50 mg/kg Pycnogenol® significantly enhanced immunoreactivity of antioxidant enzymes (superoxide dismutases and catalase) in the pyramidal cells before and after TFI induction. Furthermore, the treatment significantly reduced the generation of superoxide anion, ribonucleic acid oxidation and lipid peroxidation in the pyramidal cells. Moreover, interestingly, its neuroprotective effect was abolished by administration of sodium azide (a potent inhibitor of SODs and catalase activities). Taken together, current results clearly indicate that Pycnogenol® supplementation can prevent neurons from ischemic stroke through its potent antioxidative role.

Long-term consumption of virgin coconut (Cocos nucifera) oil diet impairs learning and memory in CD1 mice

ObjectiveVirgin coconut oil (VCO) has been used in the management of dementia in Alzheimer’s disease (AD). Therefore, this research investigated the effect of long-term consumption of VCO diet on learning and memory in CD1 mice. MethodsThirty male CD1 mice (divided into three groups, n = 10) were fed with standard rodent chow (control), 5% and 20% VCO diets (respectively) for 28 d. The Morris Water Maze (MWM) test was used to test the effect of VCO on visuo-spatial learning and memory, while the Novel Object Recognition Test (NORT) was used to measure short- and long-term recognition memory. ResultsLearning performance of mice did not differ in the MWM. During the probe trial, duration in the retention quadrant and annulus crossings were lower (P < 0.05) in the 5% and 20% VCO diet groups compared to the control diet group, showing that VCO impaired visuo-spatial memory. During the NORT, mice showed more total approaches in the 20% VCO diet group (P < 0.05) compared to control and the 5% VCO diet groups during the short-term memory test. During the long-term memory retention test, the total approaches were also higher in the 20% VCO group compared to control and 5% VCO group (P > 0.05). The discrimination index was also lower in the 20% VCO group compared to control and 5% VCO diet groups indicating impaired long-term cognitive memory in mice given 20% VCO diet. Histological examination of brains showed damage within the CA1 pyramidal cell layer of the hippocampus in the 20% VCO diet group, in line with the behavioural observations. ConclusionLong-term consumption of virgin coconut oil diet impairs memory in mice.

Extracellular GABA waves regulate coincidence detection in excitatory circuits.

Key points Rapid changes in neuronal network activity trigger widespread waves of extracellular GABA in hippocampal neuropil.Elevations of extracellular GABA narrow the coincidence detection window for excitatory inputs to CA1 pyramidal cells.GABA transporters control the effect of extracellular GABA on coincidence detection.Small changes in the kinetics of dendritic excitatory currents amplify when reaching the soma. Coincidence detection of excitatory inputs by principal neurons underpins the rules of signal integration and Hebbian plasticity in the brain. In the hippocampal circuitry, detection fidelity is thought to depend on the GABAergic synaptic input through a feedforward inhibitory circuit also involving the hyperpolarisation‐activated Ih current. However, afferent connections often bypass feedforward circuitry, suggesting that a different GABAergic mechanism might control coincidence detection in such cases. To test whether fluctuations in the extracellular GABA concentration [GABA] could play a regulatory role here, we use a GABA 'sniffer' patch in acute hippocampal slices of the rat and document strong dependence of [GABA] on network activity. We find that blocking GABAergic signalling strongly widens the coincidence detection window of direct excitatory inputs to pyramidal cells whereas increasing [GABA] through GABA uptake blockade shortens it. The underlying mechanism involves membrane‐shunting tonic GABAA receptor current; it does not have to rely on Ih but depends strongly on the neuronal GABA transporter GAT‐1. We use dendrite‐soma dual patch‐clamp recordings to show that the strong effect of membrane shunting on coincidence detection relies on nonlinear amplification of changes in the decay of dendritic synaptic currents when they reach the soma. Our results suggest that, by dynamically regulating extracellular GABA, brain network activity can optimise signal integration rules in local excitatory circuits.

Maternal Immune Activation Affects Hippocampal Excitatory and Inhibitory Synaptic Transmission in Offspring From an Early Developmental Period to Adulthood.

One of the risk factors for schizophrenia is maternal infection. We have previously shown that Polyriboinosinic-polyribocytidylic acid (poly I:C) induced maternal immune activation in mice caused histological changes in the hippocampal CA1 area of offspring during the developmental period and impaired sensorimotor gating in offspring during adulthood, resulting in behavioral changes. However, it remains unclear how maternal immune activation functionally impacts the hippocampal neuronal activity of offspring. We studied the effect of prenatal poly I:C treatment on synaptic transmission of hippocampal CA1 pyramidal cells in postnatal and adult offspring. Treatment with poly I:C diminished excitatory and enhanced inhibitory (GABAergic) synaptic transmission on pyramidal cells in adult offspring. During the early developmental period, we still observed that treatment with poly I:C decreased excitatory synaptic transmission and potentially increased GABAergic synaptic transmission, which was uncovered under a condition of high extracellular potassium-activated neurons. In conclusion, we demonstrate that maternal immune activation decreased excitatory and increased inhibitory synaptic transmission on hippocampal pyramidal cells from an early developmental period to adulthood, which could result in net inhibition in conjunction with poor functional organization and integration of hippocampal circuits.

Afterhyperpolarization amplitude in CA1 pyramidal cells of aged Long-Evans rats characterized for individual differences

Altered neural excitability is considered a prominent contributing factor to cognitive decline during aging. A clear example is the excess neural activity observed in several temporal lobe structures of cognitively impaired older individuals in rodents and humans. At a cellular level, aging-related changes in mechanisms regulating intrinsic excitability have been well examined in pyramidal cells of the CA1 hippocampal subfield. Studies in the inbred Fisher 344 rat strain document an age-related increase in the slow afterhyperpolarization (AHP) that normally occurs after a burst of action potentials, and serves to reduce subsequent firing. We evaluated the status of the AHP in the outbred Long-Evans rat, a well-established model for studying individual differences in neurocognitive aging. In contrast to the findings reported in the Fisher 344 rats, in the Long-Evan rats we detected a selective reduction in AHP in cognitively impaired aged individuals. We discuss plausible scenarios to account for these differences and also discuss possible implications of these differences.

5-HT7 receptors increase the excitability of hippocampal CA1 pyramidal neurons by inhibiting the A-type potassium current

Accumulating evidence suggests a widespread role of serotonin 5-HT7 receptors (5-HT7Rs) in the physiology of cognitive and affective processing. However, we still lack insights into 5-HT7R electrophysiology. Studies analyzing the 5-HT7R-mediated changes in CA1 pyramidal neuron activity revealed that 5-HT7R activation leads to the opening of hyperpolarization-activated cyclic nucleotide-gated cation channels (HCNs). However, our group and others have shown that CA1 pyramidal cells increase their excitability following 5-HT7R activation, an effect which cannot be explained by HCN channel opening. This suggests a different ionic mechanism might be responsible. To investigate this, we performed whole-cell patch clamp recordings of CA1 pyramidal cells in rat brain slices. It was found that acute 5-HT7R activation increased membrane excitability and decreased spiking latency. Both effects were blocked by a selective 5-HT7R antagonist. Spike latency in CA1 pyramidal cells is known to be regulated by transient outward voltage-dependent A-type potassium channels. Subsequent voltage clamp recordings revealed that acute 5-HT7R activation inhibited A-type potassium currents. Pharmacological block of Kv4.2/4.3 potassium channel subunits prevented the 5-HT7R agonist-induced changes in excitability and spiking latency, whereas blocking HCN channels had no influence on these effects. Taken together, the results reveal an ionic mechanism previously not known to be associated with 5-HT7R activation. Inhibition of A-type potassium channels can fully account for increased CA1 pyramidal cell excitability after 5-HT7R activation. These results can help explain a number of behavioral and physiological findings and will hopefully lead to a better understanding of 5-HT7 receptor signaling in health and disease.

Oxycodone injections not paired with conditioned place preference have little effect on the hippocampal opioid system in female and male rats.

Oxycodone (Oxy) conditioned place preference (CPP) in Sprague Dawley rats results in sex-specific alterations in hippocampal opioid circuits in a manner that facilitates opioid-associative learning processes, particularly in females. Here, we examined if Oxy (3mg/kg, I.P.) or saline (Sal) injections not paired with behavioral testing similarly affect the hippocampal opioid system. Sal-injected females compared to Sal-injected males had: (1) higher densities of cytoplasmic delta opioid receptors (DOR) in GABAergic hilar dendrites suggesting higher baseline reserve DOR pools and (2) elevated phosphorylated DOR levels, but lower phosphorylated mu opioid receptor (MOR) levels in CA3a suggesting that the baseline pools of activated opioid receptors vary in females and males. In contrast to CPP studies, Oxy-injections in the absence of behavioral tests resulted in few changes in the hippocampal opioid system in either females or males. Specifically, Oxy-injected males compared to Sal-injected males had fewer DORs near the plasma membrane of CA3 pyramidal cell dendrites and in CA3 dendritic spines contacted by mossy fibers, and lower pMOR levels in CA3a. Oxy-injected females compared to Sal-injected females had higher total DORs in GABAergic dendrites and lower total MORs in parvalbumin-containing dendrites. Thus, unlike Oxy CPP, Oxy-injections redistributed opioid receptors in hippocampal neurons in a manner that would either decrease (males) or not alter (females) excitability and plasticity processes. These results indicate that the majority of changes within hippocampal opioid circuits that would promote opioid-associative learning processes in both females and males do not occur with Oxy administration alone, and instead must be paired with CPP.

Mechanisms associated with the antidepressant-like effects of L-655,708.

Previous research has demonstrated that selective modulation of hippocampal transmission by systemic administration of an α5-GABAA receptor negative allosteric modulator, L-655,708, reproduces the sustained antidepressant-like (AD-like) effect of R,S-ketamine in the absence of any psychotomimetic or abuse-related effects. Pharmacological, electrophysiological (whole-cell patch clamp), and behavioral approaches were used to examine the mechanisms by which L-655,708 produces plasticity within the hippocampus that accounts for its sustained AD-like effect in rats. Inhibitors of either transcription or translation prevented the sustained AD-like effect of L-655,708. Unlike R,S-ketamine, L-655,708 did not cause an increase in the phosphorylation of the receptor for BDNF, TrkB, in the ventral hippocampus (vHipp) 30 or 60 min after its administration nor did administration of the TrkB inhibitor, K252a, directly into the vHipp, block the sustained AD-like effect of L-655,708. Similar to previous results with R,S-ketamine, administration of L-655,709 increased levels of GluA1 in the mPFC and, blockade of such receptors by direct administration of NBQX into the mPFC blocked the sustained AD-like effect of L-655,708. Patch-clamp recordings of ventral CA1 pyramidal cells 24 h after a single systemic administration of L-655,708 revealed a significant increase in input resistance, which resulted in an approximately two-fold increase in action potential frequency. These experiments indicate that the sustained AD-like effects of L-655,708 require protein synthesis and plasticity of GluA1 glutamate receptors in the mPFC. The drug also caused changes in GABAA receptor gating properties in the vHipp with resultant changes in ventral CA1 that indirectly increases neuronal excitability. Such effects likely contribute to its sustained AD-like activity.

Slow-decaying presynaptic calcium dynamics gate long-lasting asynchronous release at the hippocampal mossy fiber to CA3 pyramidal cell synapse.

Action potentials trigger two modes of neurotransmitter release, with a fast synchronous component and a temporally delayed asynchronous release. Asynchronous release contributes to information transfer at synapses, including at the hippocampal mossy fiber (MF) to CA3 pyramidal cell synapse where it controls the timing of postsynaptic CA3 pyramidal neuron firing. Here, we identified and characterized the main determinants of asynchronous release at the MF–CA3 synapse. We found that asynchronous release at MF–CA3 synapses can last on the order of seconds following repetitive MF stimulation. Elevating the stimulation frequency or the external Ca2+ concentration increased the rate of asynchronous release, thus, arguing that presynaptic Ca2+ dynamics is the major determinant of asynchronous release rate. Direct MF bouton Ca2+ imaging revealed slow Ca2+ decay kinetics of action potential (AP) burst‐evoked Ca2+ transients. Finally, we observed that asynchronous release was preferentially mediated by Ca2+ influx through P/Q‐type voltage‐gated Ca2+ channels, while the contribution of N‐type VGCCs was limited. Overall, our results uncover the determinants of long‐lasting asynchronous release from MF terminals and suggest that asynchronous release could influence CA3 pyramidal cell firing up to seconds following termination of granule cell bursting.

Reduced expression of the glucocorticoid receptor in the hippocampus of patients with drug-resistant temporal lobe epilepsy and comorbid depression.

ObjectiveDepressive disorders are common among about 50% of the patients with drug‐resistant temporal lobe epilepsy (TLE). The underlying etiology remains elusive, but hypothalamus‐pituitary‐adrenal (HPA) axis activation due to changes in glucocorticoid receptor (GR) protein expression could play an important role. Therefore, we set out to investigate expression of the GR in the hippocampus, an important brain region for HPA axis feedback, of patients with drug‐resistant TLE, with and without comorbid depression.MethodsGR expression was studied using immunohistochemistry on hippocampal sections from well‐characterized TLE patients with depression (TLE + D, n = 14) and without depression (TLE − D, n = 12) who underwent surgery for drug‐resistant epilepsy, as well as on hippocampal sections from autopsy control cases (n = 9). Video–electroencephalography (EEG), magnetic resonance imaging (MRI), and psychiatric and memory assessments were performed prior to surgery.ResultsAbundant GR immunoreactivity was present in dentate gyrus granule cells and CA1 pyramidal cells of controls. In contrast, neuronal GR expression was lower in patients with TLE, particularly in the TLE + D group. Quantitative analysis showed a smaller GR+ area in TLE + D as compared to TLE − D patients and controls. Furthermore, the ratio between the number of GR+/NeuN+ cells was lower in patients with TLE + D as compared to TLE − D and correlated negatively with the depression severity based on psychiatric history. The expression of the GR was also lower in glial cells of TLE + D compared to TLE − D patients and correlated negatively to the severity of depression.SignificanceReduced hippocampal GR expression may be involved in the etiology of depression in patients with TLE and could constitute a biological marker of depression in these patients.

Distribution of VTA Glutamate and Dopamine Terminals, and their Significance in CA1 Neural Network Activity

Reciprocal connection between the ventral tegmental area (VTA) and the hippocampus forms a loop that controls information entry into long-term memory. Compared with the widely studied VTA dopamine system, VTA glutamate terminals are anatomically dominant in the hippocampus and less understood. The current study employs anterograde and retrograde labeling of VTA dopamine and glutamate neurons to map the distribution of their terminals within the layers of the hippocampus. Also, functional tracing of VTA dopamine and glutamate projections to the hippocampus was performed by photostimulation of VTA cell bodies during CA1 extracellular voltage sampling in vivo. VTA dopamine terminals predominantly innervate the CA1 basal dendrite layer and modulate the firing rate of active putative neurons. In contrast, anatomical dominance of VTA glutamate terminals in the CA1 pyramidal cell and apical dendrite layers suggests the possible involvement of these terminals in excitability regulation. In support of these outcomes, photostimulation of VTA dopamine neurons increased the firing rate but not intrinsic excitability parameters for putative pyramidal units. Conversely, activation of VTA glutamate neurons increased CA1 network firing rate and burst rate. In addition, VTA glutamate inputs reduced the interspike and interburst intervals for putative CA1 neurons. Taken together, we deduced that layer-specific distribution of presynaptic dopamine and glutamate terminals in the hippocampus determinines VTA modulation (dopamine) or regulation (glutamate) of excitability in the CA1 neural network.