CALHM1 deficiency impairs cerebral neuron activity and memory flexibility in mice

Abstract

1CALHM1 is a cell surface calcium channel expressed in cerebral neurons. CALHM1 function in the brain remains unknown, but recent results showed that neuronal CALHM1 controls intracellular calcium signaling and cell excitability, two mechanisms required for synaptic function. Here, we describe the generation of Calhm1 knockout (Calhm1 −/− ) mice and investigate CALHM1 role in neuronal and cognitive functions. Structural analysis revealed that Calhm1 −/− brains had normal regional and cellular architecture, and showed no evidence of neuronal or synaptic loss, indicating that CALHM1 deficiency does not affect brain development or brain integrity in adulthood. However, Calhm1 −/− mice showed a severe impairment in memory flexibility, assessed in the Morris water maze, and a significant disruption of long-term potentiation without alteration of long-term depression, measured in ex vivo hippocampal slices. Importantly, in primary neurons and hippocampal slices, CALHM1 activation facilitated the phosphorylation of NMDA and AMPA receptors by protein kinase A. Furthermore, neuronal CALHM1 activation potentiated the effect of glutamate on the expression of c-Fos and C/EBPβ, two immediateearly gene markers of neuronal activity. Thus, CALHM1 controls synaptic activity in cerebral neurons and is required for the flexible processing of memory in mice. These results shed light on CALHM1 physiology in the mammalian brain.

Post‐translational palmitoylation controls the voltage gating and lipid raft association of the CALHM1 channel

“…) and memory flexibility (Vingtdeux et al . ) in mice, suggesting that CALHM1 proteins are indeed expressed and function in the brain including cortical neurons. It is conceivable that palmitoylation could occur on CALHM1 in neurons and be important in neuronal physiology and pathophysiology because all the DHHC PATs for CALHM1 identified in this study are expressed in the brain including neurons (Korycka et al .…”

“…; Vingtdeux et al . ). In the tongue, CALHM1 activation in taste cells following a taste‐evoked action potential burst mediates purinergic neurotransmission of sweet, bitter and umami tastes, in which ATP released from CALHM1 in taste cells serves as the primary neurotransmitter to the afferent gustatory nerve terminals expressing P2X 2/3 receptors (Taruno et al .…”

Molecular and Pharmacological Modulation of CALHM1 Promote Neuroprotection against Oxygen and Glucose Deprivation in a Model of Hippocampal Slices

“…In view of the physiological role of CALHM1 in the regulation of AMPA and NMDA receptor expression and its implication in memory consolidation in the hippocampus [19], as well as, the participation of CALHM1 in the maintenance of neuronal excitability [17], we decided to perform our experiments in brain hippocampal slices from Calhm1 +/+ , Calhm1 +/− and Calhm1 −/− mice. In this study, we have performed experiments with Calhm1 +/− mice, showing that the deletion of just one allele of CALHM1 results neuroprotective in the OGD/Reox protocol.…”

“…Also, CALHM1 participates in taste perception, acting as an ATP-releasing channel from type 2 taste bud cells [18].CALHM1 is implicated in the Long-Term Potentiation (LTP) process, the molecular mechanism involved in learning and memory formation in the brain. Its opening triggers an increase in the phosphorylation of AMPA and NMDA receptors, promoting its trafficking to the plasma membrane, making them functional [19].Lastly, CALHM1 has been implicated in brain ischemia. In Calhm1 −/− mice, the infarct volume after middle cerebral artery occlusion (MCAO) is significantly lower compared to wild-type mice.…”

“…CALHM1 is implicated in the Long-Term Potentiation (LTP) process, the molecular mechanism involved in learning and memory formation in the brain. Its opening triggers an increase in the phosphorylation of AMPA and NMDA receptors, promoting its trafficking to the plasma membrane, making them functional [19].…”