Endogenous cannabinoids mediate the effect of BDNF at CA1 inhibitory synapses in the hippocampus

Postsynaptic organizational protein complexes play central roles both in orchestrating synapse formation and in defining the functional properties of synaptic transmission that together shape the flow of information through neuronal networks. A key component of these organizational protein complexes is the family of synaptic adhesion proteins called neuroligins. Neuroligins form transsynaptic bridges with presynaptic neurexins to regulate various aspects of excitatory and inhibitory synaptic transmission. Neuroligin-2 (NLGN2) is the only member that acts exclusively at GABAergic inhibitory synapses. Altered expression and mutations in NLGN2 and several of its interacting partners are linked to cognitive and psychiatric disorders, including schizophrenia, autism, and anxiety. Research on NLGN2 has fundamentally shaped our understanding of the molecular architecture of inhibitory synapses. Here, we discuss the current knowledge on the molecular and cellular functions of mammalian NLGN2 and its role in the neuronal circuitry that regulates behavior in rodents and humans.

Download Full-text

CB1 antagonism increases excitatory synaptogenesis in a cortical spheroid model of fetal brain development

Scientific Reports ◽

10.1038/s41598-021-88750-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Alexis Papariello ◽

David Taylor ◽

Ken Soderstrom ◽

Karen Litwa

Keyword(s):

Brain Development ◽

Spontaneous Activity ◽

Microelectrode Array ◽

Cannabinoid Receptor ◽

Fetal Brain ◽

Endocannabinoid System ◽

Autism Spectrum ◽

Nervous System Development ◽

Inhibitory Synapses ◽

Fetal Brain Development

AbstractThe endocannabinoid system (ECS) plays a complex role in the development of neural circuitry during fetal brain development. The cannabinoid receptor type 1 (CB1) controls synaptic strength at both excitatory and inhibitory synapses and thus contributes to the balance of excitatory and inhibitory signaling. Imbalances in the ratio of excitatory to inhibitory synapses have been implicated in various neuropsychiatric disorders associated with dysregulated central nervous system development including autism spectrum disorder, epilepsy, and schizophrenia. The role of CB1 in human brain development has been difficult to study but advances in induced pluripotent stem cell technology have allowed us to model the fetal brain environment. Cortical spheroids resemble the cortex of the dorsal telencephalon during mid-fetal gestation and possess functional synapses, spontaneous activity, an astrocyte population, and pseudo-laminar organization. We first characterized the ECS using STORM microscopy and observed synaptic localization of components similar to that which is observed in the fetal brain. Next, using the CB1-selective antagonist SR141716A, we observed an increase in excitatory, and to a lesser extent, inhibitory synaptogenesis as measured by confocal image analysis. Further, CB1 antagonism increased the variability of spontaneous activity within developing neural networks, as measured by microelectrode array. Overall, we have established that cortical spheroids express ECS components and are thus a useful model for exploring endocannabinoid mediation of childhood neuropsychiatric disease.

Download Full-text

Type IIa RPTPs and Glycans: Roles in Axon Regeneration and Synaptogenesis

International Journal of Molecular Sciences ◽

10.3390/ijms22115524 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5524

Author(s):

Kazuma Sakamoto ◽

Tomoya Ozaki ◽

Yuji Suzuki ◽

Kenji Kadomatsu

Keyword(s):

Heparan Sulfate ◽

Network Formation ◽

Synapse Formation ◽

Axon Regeneration ◽

Transmembrane Protein ◽

Inhibitory Synapses ◽

Dependent Manner ◽

Axon Terminals ◽

Axon Extension ◽

Receptor Tyrosine Phosphatases

Type IIa receptor tyrosine phosphatases (RPTPs) play pivotal roles in neuronal network formation. It is emerging that the interactions of RPTPs with glycans, i.e., chondroitin sulfate (CS) and heparan sulfate (HS), are critical for their functions. We highlight here the significance of these interactions in axon regeneration and synaptogenesis. For example, PTPσ, a member of type IIa RPTPs, on axon terminals is monomerized and activated by the extracellular CS deposited in neural injuries, dephosphorylates cortactin, disrupts autophagy flux, and consequently inhibits axon regeneration. In contrast, HS induces PTPσ oligomerization, suppresses PTPσ phosphatase activity, and promotes axon regeneration. PTPσ also serves as an organizer of excitatory synapses. PTPσ and neurexin bind one another on presynapses and further bind to postsynaptic leucine-rich repeat transmembrane protein 4 (LRRTM4). Neurexin is now known as a heparan sulfate proteoglycan (HSPG), and its HS is essential for the binding between these three molecules. Another HSPG, glypican 4, binds to presynaptic PTPσ and postsynaptic LRRTM4 in an HS-dependent manner. Type IIa RPTPs are also involved in the formation of excitatory and inhibitory synapses by heterophilic binding to a variety of postsynaptic partners. We also discuss the important issue of possible mechanisms coordinating axon extension and synapse formation.

Download Full-text

The α3 subunit of GABAA receptors promotes formation of inhibitory synapses in the absence of collybistin

Journal of Biological Chemistry ◽

10.1016/j.jbc.2021.100709 ◽

2021 ◽

pp. 100709

Author(s):

Sven Wagner ◽

ChoongKu Lee ◽

Lucia Rojas ◽

Christian G. Specht ◽

JeongSeop Rhee ◽

...

Keyword(s):

Gabaa Receptors ◽

Inhibitory Synapses ◽

Α3 Subunit

Download Full-text

The role of GABAA receptor biogenesis, structure and function in epilepsy

Biochemical Society Transactions ◽

10.1042/bst0340863 ◽

2006 ◽

Vol 34 (5) ◽

pp. 863-867 ◽

Cited By ~ 14

Author(s):

S. Mizielinska ◽

S. Greenwood ◽

C.N. Connolly

Keyword(s):

Gabaa Receptor ◽

Structure And Function ◽

Inhibitory Synapses ◽

Normal Brain ◽

Synaptic Targeting ◽

Acid Type ◽

Normal Brain Function ◽

And Function ◽

The Brain

Maintaining the correct balance in neuronal activation is of paramount importance to normal brain function. Imbalances due to changes in excitation or inhibition can lead to a variety of disorders ranging from the clinically extreme (e.g. epilepsy) to the more subtle (e.g. anxiety). In the brain, the most common inhibitory synapses are regulated by GABAA (γ-aminobutyric acid type A) receptors, a role commensurate with their importance as therapeutic targets. Remarkably, we still know relatively little about GABAA receptor biogenesis. Receptors are constructed as pentameric ion channels, with α and β subunits being the minimal requirement, and the incorporation of a γ subunit being necessary for benzodiazepine modulation and synaptic targeting. Insights have been provided by the discovery of several specific assembly signals within different GABAA receptor subunits. Moreover, a number of recent studies on GABAA receptor mutations associated with epilepsy have further enhanced our understanding of GABAA receptor biogenesis, structure and function.

Download Full-text