Secretagogin marks amygdaloid PKCδ interneurons and modulates NMDA receptor availability.

The perception of and response to danger is critical for an individual's survival and is encoded by subcortical neurocircuits. The amygdaloid complex is the primary neuronal site that initiates bodily reactions upon external threat with local-circuit interneurons scaling output to effector pathways. Here, we categorize central amygdala neurons that express secretagogin (Scgn), a Ca2+-sensor protein, as a subset of protein kinase Cδ (PKCδ)+ interneurons, likely "off cells." Chemogenetic inactivation of Scgn+/PKCδ+ cells augmented conditioned response to perceived danger in vivo. While Ca2+-sensor proteins are typically implicated in shaping neurotransmitter release presynaptically, Scgn instead localized to postsynaptic compartments. Characterizing its role in the postsynapse, we found that Scgn regulates the cell-surface availability of NMDA receptor 2B subunits (GluN2B) with its genetic deletion leading to reduced cell membrane delivery of GluN2B, at least in vitro. Conclusively, we describe a select cell population, which gates danger avoidance behavior with secretagogin being both a selective marker and regulatory protein in their excitatory postsynaptic machinery.

Distribution and classification of the extracellular matrix in the olfactory bulb.

Extracellular matrix (ECM) became an important player over the last few decades when studying the plasticity and regeneration of the central nervous system. In spite of the established role of ECM in these processes throughout the central nervous system (CNS), only few papers were published on the ECM of the olfactory system, which shows a lifelong plasticity, synaptic remodeling and postnatal neurogenesis. In the present study, we have described the localization and organization of major ECM molecules, the hyaluronan, the lecticans, tenascin-R and HAPLN1 link protein in the olfactory bulb (OB) of the rat. We detected all of these molecules in the OB showing differences in the molecular composition, staining intensity, and organization of ECM between the layers and in some cases within a single layer. One of the striking features of ECM staining pattern in the OB was that the reactions are shown dominantly in the neuropil, the PNNs were found rarely and they exhibited thin or diffuse appearance Similar organization was shown in human and mice samples. As the PNN limits the neural plasticity, its rare appearance may be related to the high degree of plasticity in the OB.

Revival of calcium-binding proteins for neuromorphology: secretagogin typifies distinct cell populations in the avian brain.

In the vertebrate nervous system, the Ca(2+)-binding proteins parvalbumin, calbindin and calretinin have been extensively used to elaborate the molecular diversity of neuronal subtypes. Secretagogin is a phylogenetically conserved Ca(2+)-binding protein, which marks neuronal populations largely distinct from other Ca(2+)-binding proteins in mammals. Whether secretagogin is expressed in nonmammalian vertebrates, particularly in birds, and, if so, with a brain cytoarchitectonic design different from that of mammals is unknown. Here, we show that secretagogin is already present in the hatchlings' brain with continued presence into adulthood. Secretagogin-immunoreactive neurons primarily accumulate in the olfactory bulb, septum, subpallial amygdala, hippocampus, hypothalamus, habenular nuclei and deep layers of the optic tectum of adult domestic chicks (Gallus domesticus). In the olfactory bulb, secretagogin labels periglomerular neurons as well as a cell continuum ascending dorsomedially, reaching the ventricular wall. Between the hippocampus and septal nuclei, the interconnecting thin septal tissue harbors secretagogin-immunoreactive neurons that contact the ventricular wall with their ramifying dendritic processes. Secretagogin is also present in the neuroendocrine hypothalamus, with particularly rich neuronal clusters seen in its suprachiasmatic and infundibular nuclei. Secretagogin expression identified a hitherto undescribed cell contingent along intratelencephalic cell-free laminae separating brain regions or marking the palliosubpallial boundary, as well as a dense neuronal population in the area corticoidea lateralis. In both the telencephalon and midbrain, secretagogin complemented the distribution of the canonical 'neuronal' Ca(2+)-binding proteins. Our findings identify novel neuronal subtypes, connectivity patterns in brain areas functionally relevant to olfaction, orientation, behavior as well as endocrine functions, which will help refine existing concepts on the neuronal diversity and organizational principles of the avian brain.

[The "dress" makes the neuron -- different forms of the extracellular matrix in the central nervous system of vertebrates]. / A "ruha" teszi a neuront -- az extracelluláris mátrix különbözo megjelenési formái gerincesek központi idegrendszerében.

INTRODUCTION: Extracellular matrix is a key component of most connective tissues. For decades, the presence of this chemically heterogeneous interface has been largely ignored or even denied in the central nervous system. It was not until the end of the last century that scientists turned their attention to this enigmatic substance and unravelled its versatile roles in the developing as well as the adult nervous system. AIM: The aim of the authors was to characterize different parts of the human central nervous system: the hippocampus, the lateral geniculate nucleus and the spinal cord. In addition they looked for connections between brain plasticity and extracellular matrix indifferent animal models. METHOD: The authors used two perfusion fixed human brain and spinal cord samples, 23 further human brain samples for disease-related investigations, 16 adult rat brains and 18 chicken brains of hatchlings, 13 days or three months of age. They visualized the extracellular matrix via lectin- and immunohistochemistry. RESULTS: It was demonstrated that the human central nervous system shows a bewildering phenotypic versatility in its various parts. The human spinal cord harbours perineuronal nets around long-range projection neurons whilst peri-synaptic coats are enriched in the dorsal horn. Periaxonal coats protect functional synapses in neurodegeneration. In the rat thalamus, perineuronal matrix is enriched in less plastic territories and develops in accordance with its linked cortical region. In the chicken, perineuronal matrix is well established already at birth and its further development is not functionally dependent. CONCLUSIONS: In human, the perineuronal matrix shows a large diversity depending on regional distribution and function. The authors argue that the development and differentiation of extracellular matrix is strongly linked to those of neurons. This observation was based on findings in the domestic chick which exhibits an immediate maturity after hatching as well as on observations in rat thalamic nuclei which reflect the plasticity of their corresponding cortical fields.

Neurochemical mapping of the human hippocampus reveals perisynaptic matrix around functional synapses in Alzheimer's disease.

Perineuronal matrix is an extracellular protein scaffold to shape neuronal responsiveness and survival. Whilst perineuronal nets engulf the somatodendritic axis of neurons, axonal coats are focal extracellular protein aggregates surrounding individual synapses. Here, we addressed the chemical identity and subcellular localization of both perineuronal and perisynaptic matrices in the human hippocampus, whose neuronal circuitry is progressively compromised in Alzheimer's disease. We hypothesized that (1) the cellular expression sites of chondroitin sulphate proteoglycan-containing extracellular matrix associate with specific neuronal identities, reflecting network dynamics, and (2) the regional distribution and molecular composition of axonal coats must withstand Alzheimer's disease-related modifications to protect functional synapses. We show by epitope-specific antibodies that the perineuronal protomap of the human hippocampus is distinct from other mammals since pyramidal cells but not calretinin(+) and calbindin(+) interneurons, neurochemically classified as novel neuronal subtypes, lack perineuronal nets. We find that cartilage link protein-1 and brevican-containing matrices form isolated perisynaptic coats, engulfing both inhibitory and excitatory terminals in the dentate gyrus and entorhinal cortex. Ultrastructural analysis revealed that presynaptic neurons contribute components of perisynaptic coats via axonal transport. We demonstrate, by combining biochemical profiling and neuroanatomy in Alzheimer's patients and transgenic (APdE9) mice, the preserved turnover and distribution of axonal coats around functional synapses along dendrite segments containing hyperphosphorylated tau and in amyloid-ß-laden hippocampal microdomains. We conclude that the presynapse-driven formation of axonal coats is a candidate mechanism to maintain synapse integrity under neurodegenerative conditions.

Activity-induced dendrite and dendritic spine development in human amyloid precursor protein transgenic mice.

The amyloid precursor protein is essential for proper neuronal function but an imbalance in processing or metabolism or its overexpression lead to severe malfunction of the brain. The present study focused on dendritic morphology of hippocampal neurons in mice overexpressing the wild-type human amyloid precursor protein (hAPP). In addition, we examined whether enhanced physical activity may affect hAPP-related morphological changes. Overexpression of hAPP resulted in significant enlargement of dendrites, especially within the basal dendritic field but had no effect on spine density. Enhanced physical activity only moderately potentiated hAPP induced changes in dendritic size. Physical activity dependent increases in spine density were, however, augmented by hAPP overexpression. The results suggest that enhanced levels of wild-type hAPP do not result in degenerative changes of neuronal morphology, but rather promote dendritic growth.

Distribution and classification of aggrecan-based extracellular matrix in the thalamus of the rat.

Extracellular matrix molecules take part in functional isolation and stabilization of neuronal compartments but form a vivid interface between neuronal elements at the same time. Previous studies have shown that the accumulation of extracellular matrix, especially its typical phenotypic form, termed perineuronal nets, correlates not only with the functional properties of the single neuron but also with the functional properties of the whole brain area. In contrast to recent advances in investigating neocortex, the present study mapped the occurrence and phenotypic appearance of aggrecan-based matrix accumulation throughout the rat thalamus. Results showed that divisions of thalamus that relay information to cortical fields known rather for their plastic properties exibit a poor matrix immunoreactivity, whereas matrix accumulation is more enhanced in nuclei connected to primary cortical regions. In addition to perineuronal nets, extracellular matrix condensed in another peculiar form, in 2-5-µm, large, round or oval structures, as described by Brückner et al. ([ 2008] Neuroscience 151:489-504) as axonal coats (ACs). Multiple labelling experiments showed that specific excitatory afferents were not ensheathed with these structures. At the same time, inhibitory endings were occasionally enwrapped in ACs. Electron microscopic analysis showed that aggrecan-immunoreactive profiles were present mostly around inhibitory terminals but also in all neuronal compartments. We suggest that aggrecan-based extracellular matrix is formed by both pre- and postsynaptic elements and is preferably associated with inhibitory terminals in the extracellular space.