Impairment of Select Forms of Spatial Memory and Neurotrophin-Dependent Synaptic Plasticity by Deletion of Glial Aquaporin-4

Abstract

Aquaporin-4 (AQP4) is the major water channel in the central nervous system (CNS) and is primarily expressed in astrocytes. Little is known about the potential for AQP4 to influence synaptic plasticity, although many studies have shown that it regulates the response of the CNS to injury. Therefore, we evaluated long-term potentiation (LTP), and long-term depression (LTD) in AQP4 knockout (KO) and wild type (WT) mice. KO mice exhibited a selective defect in LTP and LTD without a change in basal transmission or short-term plasticity. Interestingly, the impairment in LTP in KO mice was specific for the type of LTP that depends on the neurotrophin BDNF, which is induced by stimulation at theta rhythm (TBS-LTP), but there was no impairment in a form of LTP that is BDNF-independent, induced by high frequency stimulation (HFS-LTP). LTD was also impaired in KO mice, which was rescued by a scavenger of BDNF or blockade of Trk receptors. TrkB receptors, which mediate effects of BDNF on TBS-LTP, were not altered in KO mice, but p75NTR, the receptor that binds all neurotrophins and has been implicated in some types of LTD, was decreased. The KO mice also exhibited a cognitive defect, which suggests a new role for AQP4 and astrocytes in normal cognitive function. This defect was evident using a test for location-specific object memory but not Morris water maze or contextual fear conditioning. The results suggest that AQP4 channels in astrocytes play an unanticipated role in neurotrophin-dependent plasticity and influence behavior.

Aquaporin-4 Deficiency Impairs Synaptic Plasticity and Associative Fear Memory in the Lateral Amygdala: Involvement of Downregulation of Glutamate Transporter-1 Expression

“…In this study, we found that the freezing behavior of AQP4 KO mice significantly reduced 24 h after training without any significant difference during the training and 2 h after training when compared with that of WT mice, indicating that AQP4 deficiency impairs the consolidation of associative fear memory without altering the normal acquisition of fear memory. Interestingly, it was reported that AQP4 deficiency had no effect on contextual fear memory (Skucas et al, 2011), which seems inconsistent with our result. In fact, these results are not contradictory.…”

“…In general, increasing glutamate release or reducing glutamate uptake can alter basal synaptic transmission. However, we found that AQP4 deficiency reduced GLT-1 expression, which accordingly reduced glutamate uptake, but failed to have a major effect on basal synaptic transmission, as reported by Skucas et al (2011). One possible reason for this is that AQP4 deficiency reduces neuronal excitability by expanding ECS volume (Binder et al, 2004(Binder et al, , 2006, which has been demonstrated to play an important role in cell-cell communication and extracellular buffering of ions such as K + and glutamate.…”

“…Therefore, the impairment of LTP in AQP4 KO mice is due to the changes in postsynaptic response to glutamate. Notably, Skucas et al (2011) recently reported that AQP4 KO impaired the TBS-induced LTP, but exhibited the normal LTP induced by HFS in hippocampal slices. In contrast, we found that AQP4 deficiency impaired the HFSinduced LTP in the thalamo-LA pathway.…”

Water diffusion reveals networks that modulate multiregional morphological plasticity after repetitive brain stimulation

“…It is also possible that dynamical coupling in the morphology of microstructures allows the formation of networks to represent the plasticity-related morphological changes following brain stimulation protocols. The morphology of dendritic spines can modulate synaptic efficacy and plasticity (3,4,38); therefore, it is possible that the nodes in the identified networks can indirectly achieve long-distance coupling with each other by modulating synaptic plasticity or efficacy of the transsynaptic signaling (39).…”

“…R epetitive electrical brain stimulation induces long-term potentiation (LTP) or depression (LTD) at the stimulated neurons (1)(2)(3)(4). In humans, repetitive transcranial magnetic stimulation (rTMS) alters cortical excitability at the stimulated site that outlasts the end of the stimulation, analogous to LTP or LTD in animal models (5,6), but also affects remote regions, possibly through transsynaptic pathways (7,8).…”