Work

NCKX4 regulates hippocampal Ca2+ homeostasis and contributes to contextual memory and anxiety-related behaviours

Year: 2026

Type: article

Abstract: The K⁺-dependent Na⁺/Ca²⁺-exchanger (NCKX) family comprises five members (NCKX1–5) that serve as key regulators of Ca²⁺ homeostasis. The fourth member, NCKX4, has been implicated in several neuronal processes, including vision, olfaction, and hypothalamic satiety signaling. We recently showed high NCKX4 expression in the mossy fibers of the hippocampus, a brain region essential for learning and memory. In this study, we investigated the impact of NCKX4 loss on Ca²⁺ dynamics in primary hippocampal neurons and assessed hippocampal-dependent behaviour in Nckx4 –/– mice. Using Ca 2+ imaging, we found that NCKX4 actively contributes to Ca²⁺ homeostasis in hippocampal cells and its loss is not compensated for by other Ca 2+ transporters. Neurons lacking NCKX4 had significantly reduced rates of total Na + /Ca 2+ -exchange activity and showed a decrease in the rate of Ca 2+ clearance following a depolarization event. Complementary behavioural testing showed deficits in contextual memory formation and recall, as well as reduced anxiety when placed in an open field, in Nckx4 –/– mice. These findings reveal a previously unrecognized role for NCKX4 in regulating hippocampal Ca 2+ dynamics, and support the hypothesis that NCKX4 expression is mechanistically linked to learning and memory.

Source: Cell Calcium

DOI: 10.1016/j.ceca.2026.103126

Authors: Mohamed Tarek Hassan, Guilherme Henrique Souza Bomfim, Nish Patel, Sarvan Kumar Radhakrishnan, Rodrigo S. Lacruz, Jonathan Lytton

Institutions: University of Calgary, Hotchkiss Brain Institute, Libin Cardiovascular Institute of Alberta, New York University

Language: English

Topic: Memory and Neural Mechanisms

Subfield: Cognitive Neuroscience

Field: Neuroscience

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,950