Layer- and Cell Type-Specific Modulation of Excitatory Neuronal Activity in the Neocortex

Abstract

From an anatomical point of view the neocortex is subdivided into up to six layers depending on the cortical area. This subdivision has been described already by Meynert and Brodmann in the late 19/early 20. century and is mainly based on cytoarchitectonic features such as the size and location of the pyramidal cell bodies. Hence, cortical lamination is originally an anatomical concept based on the distribution of excitatory neuron. However, it has become apparent in recent years that apart from the layer-specific differences in morphological features, many functional properties of neurons are also dependent on cortical layer or cell type. Such functional differences include changes in neuronal excitability and synaptic activity by neuromodulatory transmitters. Many of these neuromodulators are released from axonal afferents from subcortical brain regions while others are released intrinsically. In this review we aim to describe layer- and cell-type specific differences in the effects of neuromodulator receptors in excitatory neurons in layers 2–6 of different cortical areas. We will focus on the neuromodulator systems using adenosine, acetylcholine, dopamine, and orexin/hypocretin as examples because these neuromodulator systems show important differences in receptor type and distribution, mode of release and functional mechanisms and effects. We try to summarize how layer- and cell type-specific neuromodulation may affect synaptic signaling in cortical microcircuits.

Ectopic HCN4 expression drives mTOR-dependent epilepsy

“…Outward currents could not be examined in Rheb CA neurons due to poor space clamp leading to unclamped firing upon depolarizing voltage pulses. Due to the large increase in Rheb CA neuron size, it was not surprising to find larger Kir-mediated currents, which are well-known to be expressed in control layer 2/3 pyramidal neurons as G protein inwardly rectifying K channels (46,47). However, finding HCN-mediated currents was surprising because control layer 2/3 pyramidal neurons are not known to express such currents, as confirmed here.…”

“…Identifying a cAMP-dependent excitability in Rheb CA neurons is tantalizing because cortical pyramidal neurons receive multiple inputs that activate receptors leading to cAMP increases. These inputs include noradrenergic and dopaminergic innervation from the locus coeruleus (e.g., (49,50)) and the ventral tegmental area (e.g., Gscoupled β1-and β2-adrenergic receptors and D1 and D5 receptors, see (47,51) for references).…”

Transcriptome-scale spatial gene expression in the human dorsolateral prefrontal cortex

“…Based on examination of its histological organization and cytoarchitecture, the neocortex can be divided into six layers. Histological layers contain multiple cell types, including excitatory neurons, inhibitory neurons, and glia, and layers can be differentiated based on cell type composition and density, as well as morphology and connectivity of resident cell types (DeFelipe and Fariñas, 1992;Harris and Shepherd, 2015;Narayanan et al, 2017;Radnikow and Feldmeyer, 2018) . Studies of postmortem brains from individuals with neuropsychiatric disorders have identified disease-associated changes in gene expression and synaptic structure that can be spatially localized to different cortical laminae (Sweet et al, 2010;Velmeshev et al, 2019) .…”

“…The spatial organization of the brain is fundamentally related to its function. This structure-function relationship is especially apparent in the context of the laminar organization of the human cerebral cortex where cells residing within different cortical layers show distinct gene expression patterns and exhibit differing patterns of morphology, physiology, and connectivity (DeFelipe and Fariñas, 1992;Harris and Shepherd, 2015;Narayanan et al, 2017;Radnikow and Feldmeyer, 2018) . To the extent that structure entrains function, understanding normal brain development as well as disorders of the central nervous system will require identifying the cell types that make up the brain, and ultimately linking functional correlates of individual cell classes with structural architecture.…”

<p>The Role of Selected Pro-Inflammatory Cytokines in Pathogenesis of Ischemic Stroke</p>

“…106,107 An increased expression of mRNA for the CCL5 (RANTES) protein was recently noted in the neurons producing dopamine. 108 Chemokines show specificity for different types of leukocytes, which is particularly important in pathological conditions. Their contribution has been found in, eg, cardiovascular diseases, strokes and many inflammatory and autoimmune diseases, as well as in brain damage.…”