Hippocampus, Behavior and Disease: Focus on Neuromodulators and Intercellular Communication

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Background

The hippocampus plays a crucial role in higher brain functions like learning, memory and emotional processing. Proper communication between the different hippocampal cell types is crucial for this complex task. Thus, a complex network of neuromodulators – opioids, endocannabinoids, adenosine triphosphate among others – enables the fine tuning of intrahippocampal signalling networks. Disturbed activity of these neuromodulator systems impairs hippocampal signalling, which may lead to the development of epilepsy, cognitive and mood disorders. However, the exact role of specific neuromodulators in the development of intercellular communication, in the pathogenesis of specific diseases is not fully known. The present Research Topic summarizes the latest results in this exiting area on different levels of signalling.

On the receptor level we show how dynamic changes in receptor complexes by posttranslational modifications or by the synthesis of new receptor subunits influence learning and memory and vice versa, how memory formation influences the composition of large receptor complexes. An alternative way of receptor activity modulation is an interaction between the receptors and the extracellular ion milieu. It was previously shown that in hippocampal mood regulation both P2X7 receptors and zinc play an important role. In this Research Topic we will present how zinc and P2X7 receptors interact, and how a disturbance in this interaction may lead to mood disorder like depression.

It is well known that impaired neuron-neuron communication also contributes to the development of depression, but the exact molecular mechanism is still unclear. The major environmental factor, which precipitates depression is stress. In this Topic, we will discuss how the cannabinoid system influence stress sensitivity thus susceptibility to depression and how stress itself shapes the activity of the cannabinoid system.

Major depressive disorder is often comorbid with alcohol use disorder. In this Topic we will review how common neuro-anatomic changes, alterations in neurotransmitters and neurotrophic factors underlie to the pathophysiology of depression and alcoholism.

Disturbed control of neuronal activity may lead to epilepsy. We will present the role of opioid system in temporal lobe epilepsy with a specific focus on its functional role and therapeutic potential.

Besides opioids, also the endocannabinoids have antiepileptic properties by influencing the electrical activity of hippocampal neurons. Importantly, age influences the activity of the cannabinoid system in the hippocampus. We will present how the postnatal development influences the effect of CB1 receptors on hippocampal long-term potentiation.

The major transmitter systems are crucial not only for neuron-neuron but also in neuron-glia communication. We will show how CB1 receptor activity on GABAergic interneurons influences microglial activity highlighting the importance of GABAergic cell in microglial regulation and the specific role of CB1 receptor signalling in it.

The bidirectional interaction between astrocyte and hippocampal neurons is a key to a healthy hippocampal signalling. In this Topic, we will present an overview on dynamic ion signaling with focus on sodium and calcium in astrocytes in the hippocampus. We will highlight its relevance for neuron-glia interaction under physiological, as well as pathological, conditions like epilepsy or metabolic stress.

Keywords: epilepsy, depression, neuron-glia communication, receptor activity regulation

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