Pannexin1 Stabilizes Synaptic Plasticity and Is Needed for Learning

Abstract

Pannexin 1 (Panx1) represents a class of vertebrate membrane channels, bearing significant sequence homology with the invertebrate gap junction proteins, the innexins and more distant similarities in the membrane topologies and pharmacological sensitivities with gap junction proteins of the connexin family. In the nervous system, cooperation among pannexin channels, adenosine receptors, and KATP channels modulating neuronal excitability via ATP and adenosine has been recognized, but little is known about the significance in vivo. However, the localization of Panx1 at postsynaptic sites in hippocampal neurons and astrocytes in close proximity together with the fundamental role of ATP and adenosine for CNS metabolism and cell signaling underscore the potential relevance of this channel to synaptic plasticity and higher brain functions. Here, we report increased excitability and potently enhanced early and persistent LTP responses in the CA1 region of acute slice preparations from adult Panx1−/− mice. Adenosine application and N-methyl-D-aspartate receptor (NMDAR)-blocking normalized this phenotype, suggesting that absence of Panx1 causes chronic extracellular ATP/adenosine depletion, thus facilitating postsynaptic NMDAR activation. Compensatory transcriptional up-regulation of metabotropic glutamate receptor 4 (grm4) accompanies these adaptive changes. The physiological modification, promoted by loss of Panx1, led to distinct behavioral alterations, enhancing anxiety and impairing object recognition and spatial learning in Panx1−/− mice. We conclude that ATP release through Panx1 channels plays a critical role in maintaining synaptic strength and plasticity in CA1 neurons of the adult hippocampus. This result provides the rationale for in-depth analysis of Panx1 function and adenosine based therapies in CNS disorders.

A Germline Variant in the PANX1 Gene Has Reduced Channel Function and Is Associated with Multisystem Dysfunction

“…The pannexin family of channel-forming glycoproteins has grown in importance given their documented roles in ischemia, stroke, overactive bladder, HIV infections, Crohn's disease, platelet aggregation, and over a half-dozen other diseases (13,28,45,48,49). In most of these cases, PANX1 was identified as being the key pannexin linked to the disease, but the causal mechanism of how PANX1 large-pore channels are associated (bottom).…”

Pannexin-1 channels and their emerging functions in cardiovascular diseases

“…Several studies in the brain have shown that Pannexin-1 is involved in augmenting glutamatergic synaptic signals in the hippocampus and in pathophysiological states, such as neuronal death during stroke and dysfunction during seizure-like conditions [70][71][72][73][74]. Pannexin-1 also participates in paracrine communication between astrocytes and adjacent cells, and has been associated with ischemiainduced neuronal death and epileptic seizures [54,75].…”

A New World of Learning

“…These can be proteins that enhance connections between neurons, functioning as channels and receptors or regulating receptor activities. [35][36][37][38][39] For example, a recent study from the McGill University reveals that the plasticity of nerve cell connections in the brain is regulated by a receptor that maintains proper synapse morphology and shape. 39 The plasticity is essential for the learning processes that take place in the brain.…”

“…41 For example, the study of a research group from the University of Bochum showed that the mice without pannexin 1, a channel protein, in memory-related brain structures displayed symptoms similar to autism and that their nerve cells lacked ability to form new synaptic contacts or give up old contacts based on the level of usage. 38,40 The cell communication in general was increased to such an extent that a further increase through the learning of new knowledge was no longer possible. 38,40 It takes a lot to make a memory: new proteins have to be synthesized and neuron structures altered.…”

“…38,40 The cell communication in general was increased to such an extent that a further increase through the learning of new knowledge was no longer possible. 38,40 It takes a lot to make a memory: new proteins have to be synthesized and neuron structures altered. 42 The majority of these memory-building mechanisms are not well understood, although some of them are known, and it is still a big question how all these mechanisms are regulated.…”