Abstract
Several cytokines and chemokines are now known to play normal physiological roles in the brain where they act as key regulators of communication between neurons, glia, and microglia. In particular, cytokines and chemokines can affect cardinal cellular and molecular processes of hippocampal-dependent long-term memory consolidation including synaptic plasticity, synaptic scaling and neurogenesis. The chemokine, CX3CL1 (fractalkine), has been shown to modulate synaptic transmission and long-term potentiation (LTP) in the CA1 pyramidal cell layer of the hippocampus. Here, we confirm widespread expression of CX3CL1 on mature neurons in the adult rat hippocampus. We report an up-regulation in CX3CL1 protein expression in the CA1, CA3 and dentate gyrus (DG) of the rat hippocampus 2 h after spatial learning in the water maze task. Moreover, the same temporal increase in CX3CL1 was evident following LTP-inducing theta-burst stimulation in the DG. At physiologically relevant concentrations, CX3CL1 inhibited LTP maintenance in the DG. This attenuation in dentate LTP was lost in the presence of GABAA receptor/chloride channel antagonism. CX3CL1 also had opposing actions on glutamate-mediated rise in intracellular calcium in hippocampal organotypic slice cultures in the presence and absence of GABAA receptor/chloride channel blockade. Using primary dissociated hippocampal cultures, we established that CX3CL1 reduces glutamate-mediated intracellular calcium rises in both neurons and glia in a dose dependent manner. In conclusion, CX3CL1 is up-regulated in the hippocampus during a brief temporal window following spatial learning the purpose of which may be to regulate glutamate-mediated neurotransmission tone. Our data supports a possible role for this chemokine in the protective plasticity process of synaptic scaling.
Highlights
We identified a transient up-regulation of CX3CL1 production in the hippocampus 2 h following spatial learning or induction of long-term potentiation (LTP)
The significant training-specific up-regulations in CX3CL1, over and above those measured in passive control animals at the 2 h timepoint, implicate CX3CL1 in memory-related synaptic plasticity in the hippocampus
The enhanced glutamate neurotransmission and resultant increase in hippocampal neuronal activity associated with both spatial memory formation and LTP are the most likely drivers of the production of CX3CL1 in our studies
Summary
While higher inflammatory and pathophysiological levels of cytokines are implicated in a range of neuropsychiatric and neurodegeneration diseases, it is evident that, within the central nervous system (CNS), cytokines, including the chemoattractant cytokines (chemokines), mediate physiological signaling functions far beyond and independent of their traditional roles in inflammation and disease (Hopkins and Rothwell, 1995; Rothwell and Hopkins, 1995; Reichenberg et al, 2001; Pollmächer et al, 2002; Wilson et al, 2002; Adler and Rogers, 2005; Adler et al, 2006; McAfoose and Baune, 2009; Hoshiko et al, 2012; Williamson and Bilbo, 2013). At physiological levels, IL-1 promotes long-term potentiation (LTP), a widely employed electrophysiological model of memory-associated synaptic plasticity, whereas IL-6 appears to exert inhibitory influences on excessive excitation during LTP maintenance (Li et al, 1997; Coogan et al, 1999; Ross et al, 2003; Balschun et al, 2004). Production of both IL-1 and IL-6 is increased following LTP induction, further supporting a role for cytokines in modulating memory-associated synaptic plasticity and network-protective synaptic scaling (Schneider et al, 1998; Jankowsky et al, 2000). We investigated if CX3CL1 plays a normal physiological role in hippocampal-dependent synaptic plasticity
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