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It has been shown that subunit composition is the main determinant of the synaptic or extrasynaptic localization of GABA A receptors (GABA A Rs). Synaptic and extrasynaptic GABA A Rs are involved in phasic and tonic inhibition, respectively. It has been proposed that synaptic GABA A Rs bind to the postsynaptic gephyrin/collybistin (Geph/CB) lattice, but not the typically extrasynaptic GABA A Rs. Nevertheless, there are no studies of the direct binding of various types of GABA A Rs with the submembranous Geph/CB lattice in the absence of other synaptic proteins, some of which are known to interact with GABA A Rs. We have reconstituted GABA A Rs of various subunit compositions, together with the Geph/CB scaffold, in HEK293 cells, and have investigated the recruitment of surface GABA A Rs by submembranous Geph/CB clusters. Results show that the typically synaptic α1β3γ2 GABA A Rs were trapped by submembranous Geph/CB clusters. The α5β3γ2 GABA A Rs, which are both synaptic and extrasynaptic, were also trapped by Geph/CB clusters. Extrasynaptic α4β3δ GABA A Rs consistently showed little or no trapping by the Geph/CB clusters. However, the extrasynaptic α6β3δ, α1β3, α6β3 (and less α4β3) GABA A Rs were highly trapped by the Geph/CB clusters. AMPA and NMDA glutamate receptors were not trapped. The results suggest: (I) in the absence of other synaptic molecules, the Geph/CB lattice has the capacity to trap not only synaptic but also several typically extrasynaptic GABA A Rs; (II) the Geph/CB lattice is important but does not play a decisive role in the synaptic localization of GABA A Rs; and (III) in neurons there must be mechanisms preventing the trapping of several typically extrasynaptic GABA A Rs by the postsynaptic Geph/CB lattice., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Purinergic receptors regulate the processing of neural information in the hippocampus and cerebral cortex, structures related to cognitive functions. These receptors are activated when astrocytic and neuronal populations release adenosine triphosphate (ATP) in an autocrine and paracrine manner, following sustained patterns of neuronal activity. The modulation by these receptors of GABAergic transmission has only recently been studied. Through their ramifications, astrocytes and GABAergic interneurons reach large groups of excitatory pyramidal neurons. Their inhibitory effect establishes different synchronization patterns that determine gamma frequency rhythms, which characterize neural activities related to cognitive processes. During early life, GABAergic-mediated synchronization of excitatory signals directs the experience-driven maturation of cognitive development, and dysfunctions concerning this process have been associated with neurological and neuropsychiatric diseases. Purinergic receptors timely modulate GABAergic control over ongoing neural activity and deeply affect neural processing in the hippocampal and neocortical circuitry. Stimulation of A 2 receptors increases GABA release from presynaptic terminals, leading to a considerable reduction in neuronal firing of pyramidal neurons. A 1 receptors inhibit GABAergic activity but only act in the early postnatal period when GABA produces excitatory signals. P2X and P2Y receptors expressed in pyramidal neurons reduce the inhibitory tone by blocking GABA A receptors. Finally, P2Y receptor activation elicits depolarization of GABAergic neurons and increases GABA release, thus favoring the emergence of gamma oscillations. The present review provides an overall picture of purinergic influence on GABAergic transmission and its consequences on neural processing, extending the discussion to receptor subtypes and their involvement in the onset of brain disorders, including epilepsy and Alzheimer's disease., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), also known as β-secretase, is an aspartic protease. The sorting of this enzyme into Rab11-positive recycling endosomes regulates the BACE1-mediated cleavage of its substrates, however, the mechanisms underlying this targeting remain poorly understood. The neural cell adhesion molecule 2 (NCAM2) is a substrate of BACE1. We show that BACE1 cleaves NCAM2 in cultured hippocampal neurons and NCAM2-transfected CHO cells. The C-terminal fragment of NCAM2 that comprises the intracellular domain and a small portion of NCAM2's extracellular domain, associates with BACE1. This association is not affected in cells with inhibited endocytosis, indicating that the interaction of NCAM2 and BACE1 precedes the targeting of BACE1 from the cell surface to endosomes. In neurons and CHO cells, this fragment and BACE1 co-localize in Rab11-positive endosomes. Overexpression of full-length NCAM2 or a recombinant NCAM2 fragment containing the transmembrane and intracellular domains but lacking the extracellular domain leads to an increase in BACE1 levels in these organelles. In NCAM2-deficient neurons, the levels of BACE1 are increased at the cell surface and reduced in intracellular organelles. These effects are correlated with increased levels of the soluble extracellular domain of BACE1 in the brains of NCAM2-deficient mice, suggesting increased shedding of BACE1 from the cell surface. Of note, shedding of the extracellular domain of Sez6, a protein cleaved exclusively by BACE1, is reduced in NCAM2-deficient animals. These results indicate that the BACE1-generated fragment of NCAM2 regulates BACE1 activity by promoting the targeting of BACE1 to Rab11-positive endosomes., (© 2022. The Author(s).)