Review Hidden in the white matter: Current views on interstitial white matter neurons, 2024, Fischer and Kukley

[SNT Gatchaman]

Hidden in the white matter: Current views on interstitial white matter neurons
Maximilian Fischer; Maria Kukley

The mammalian brain comprises two structurally and functionally distinct compartments: the gray matter (GM) and the white matter (WM). In humans, the WM constitutes approximately half of the brain volume, yet it remains significantly less investigated than the GM.

The major cellular elements of the WM are neuronal axons and glial cells. However, the WM also contains cell bodies of the interstitial neurons, estimated to number 10 to 28 million in the adult bat brain, 67 million in Lar gibbon brain, and 450 to 670 million in the adult human brain, representing as much as 1.3%, 2.25%, and 3.5% of all neurons in the cerebral cortex, respectively. Many studies investigated the interstitial WM neurons (IWMNs) using immunohistochemistry, and some information is available regarding their electrophysiological properties.

However, the functional role of IWMNs in physiologic and pathologic conditions largely remains unknown. This review aims to provide a concise update regarding the distribution and properties of interstitial WM neurons, highlight possible functions of these cells as debated in the literature, and speculate about other possible functions of the IWMNs and their interactions with glial cells.

We hope that our review will inspire new research on IWMNs, which represent an intriguing cell population in the brain.

Web | DOI | PDF | The Neuroscientist | Paywall

 

[SNT Gatchaman]

One of the references in Biological Insights from Genome-Wide Association Studies and Whole Genome Sequencing of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (2026) —

The other cell type implicated by the present analysis is a population of interstitial white matter neurons (IWMNs) in the cerebellum. Abnormalities in IWMNs have been documented in several brain diseases, and a possible role in brain wiring, microcirculation, and myelination has been suggested [46]. In ME/CFS, white matter microstructural abnormalities have been reported across multiple fibre tracts, including cerebellar peduncles, and correlate with mental health and disability outcomes [47]. Whether IWMNs contribute to these abnormalities is unknown, since the investigations on the role of IWMNs in human diseases has required specific postmortem studies [46], never attempted in ME/CFS, to our knowledge.

 

[SNT Gatchaman]

Paywalled, but here are my highlighted passages —

• Both the GM and the WM contain neuronal and glial elements alongside the blood capillaries.
• density of neuronal cell bodies and synapses is significantly higher in the GM
• revealed a population of neurons residing within the WM areas of the mammalian brain, including humans … later introduced as “interstitial cells”
• Notably, WM neurons were also described in the spinal cord, the spinal nerves, and the cranial nerves
• various terms have been employed to describe them, such as WM (interstitial) cells/neurons, neurons in the WM, interstitial neurons of the WM, and interstitial or infracortical WM neurons
• we have chosen to use the name interstitial WM neurons (IWMN) and emphasize the need for a unified nomenclature.

• IWMNs remain the least studied nerve cells in the central nervous system.

• little is still known regarding the molecular properties and the functional role of IWMNs
• IWMNs arise during embryonic development and remain into adulthood and normal aging
• 450 to 670 million in the adult human brain, representing … 3.5% of the total neuron population
• Based on their location and developmental origin … superficial population encompasses the IWMNs located within the sulcal and gyral areas, directly below the sixth neocortical layer … deep population consists of IWMNs clustered in the corpus callosum, anterior commissure, internal and external capsule, and deeper parts of the WM
• Recently, some alternative hypotheses regarding the origin of IWMNs have been proposed, suggesting that IWMNs may derive from the ventral telencephalon and migrate toward the cortex or that they originate from the subependymal zone located along the wall of the lateral ventricle

• morphologically heterogeneous
• cell bodies can assume round, elongated, or pyramidal shape, and size may vary significantly
• IWMNs may elaborate few or many dendrites and may orient their dendrites parallel to the WM fibers (bipolar) or radiate them in multiple directions (multipolar).
• Smaller bipolar and fusiform neurons with fewer dendrites tend to be located deeper in the WM
• IWMNs express various neurochemical markers
  • acetylcholinesterase
  • Ca2+-binding proteins: calbindin, calretinin, and parvalbumin
  • peptide hormone cholecystokinin
  • GABA
  • microtubule associated protein (MAP2)
  • M2 muscarinic receptor
  • nitric oxide synthase (NOS)
  • somatostatin
  • tyrosine hydroxylase
• The expression of specific molecular markers is often associated with either an excitatory or an inhibitory neuronal phenotype, raising the question of whether IWMNs are excitatory (glutamatergic) or inhibitory (GABAergic).
• not fully clear … may be heterogeneous and encompass glutamatergic and GABAergic subpopulations … may be capable of co-releasing GABA and glutamate
• A recent study even suggested that co-release of glutamate and GABA may be a prevalent mode of neurotransmission in the brain

• Current knowledge regarding physiology and functions of IWMNs in the adult brain is very limited … difficulty to target
• highlight three possible functions
• regulation of excitation, inhibition, and neuronal wiring
• regulation of myelination
• regulation of microcirculation

• Taken together, electrophysiologic and morphologic data show that IWMNs … some evidence suggests that neuronal circuits involving IWMNs are plastic and dynamic
• synaptic inputs to IWMNs undergo short and long-term plasticity, indicating that synaptic strength at IWMN synapses can be modulated by neuronal activity
• In the hippocampus and cerebellum, long-term depression is thought to be an important mechanism behind learning and memory.
• whether integration of IWMNs into the neuronal circuits may be modulated by external stimuli
• proposed that during integration of subplate cells into the cortical circuitry, the rearrangement of their neurites is modulated by the sensory activity
• more and more evidence is accumulating that external behavioral stimuli modulate tissue properties not only of the GM but also of the WM and that learning correlates with structure and/or function of the WM
• It would be certainly exciting to discover the role of IWMNs during WM plasticity and to find out how various behavioral stimuli modulate their structural and functional properties as well as their connectivity.

• Many synapses in the brain are tripartite because they include not only pre- and postsynaptic neuronal elements but also the smallest processes of astrocytes
• Astrocytes perform multiple functions at synapses, including removal of neurotransmitters and release of molecules, which may modulate synaptic function … spatially segregate synapses
• Astrocytes reside also in the WM, but their structural and functional relationships with IWMNs remain unknown.
• Some IWMNs are positive for NOS and NADPH diaphorase
• NOS is an enzyme involved in the synthesis of nitric oxide, which regulates blood flow through vasodilatation. Activation of NOS is induced by the influx of calcium
• Interestingly, some NOS/NADPH expressing IWMNs are positive for neuropeptide Y, a potent vasoconstrictor
• Probably, IWMNs release nitric oxide and NPY from different compartments (cell soma vs. axons)
• contributing to the coupling of microvessels to neuronal activity

• Oligodendrocytes myelinate axons of many neurons, ensuring fast propagation of action potentials and providing tropic support for axons
• Neurons can modulate the proliferation and differentiation of developing myelinating cells, as well as the myelination process itself, through various mechanisms
• The density of oligodendroglial cells in the WM is high
• intriguing whether IWMNs also form synapses with OPCs
• and whether axon-OPC synaptic input in the WM represents a mixture of two inputs: one from the axons of long-range projection neurons located in the GM and another onefrom the axons of local IWMNs
• Two major questions
• 1) whether axons of IWMNs are myelinated
• 2) whether IWMNs can influence the function of oligodendrocytes, myelinating their own or neighboring axons.
• The rules determining this selective … myelination of some axons versus the others are not fully understood.
• for a long time, the importance of myelination has been acknowledged mainly for neurons with long axons (e.g., glutamatergic long-range projection neurons), while myelination of local neurons (e.g., GABAergic interneurons) has come to light only recently.
• it is possible that axons of many GABAergic IWMNs stay unmyelinated

• Reelin is a large extracellular matrix glycoprotein that controls cell-cell interactions and regulates neuronal migration in the developing brain.
• In the superficial WM of patients with schizophrenia, IWMNs are increased in density and express less reelin mRNA, suggesting a link between these two types of alterations
• Reelin level has not been analyzed specifically in the IWMNs of patients with autism/ASD, but reelin expression levels are lower in the parietal cortex, superior frontal cortex, and cerebellum of those patients
• The DISC1 gene is also of relevance for schizophrenia and ASD. DISC1 and its binding partners are involved in regulation of various cellular functions, including neuronal migration, neurite outgrowth, axonal extension, motility of mitochondria, synaptic plasticity, and development and function of glial cells