Abstract
Insulin induces long-term depression (insulin-LTD) in the CA1 region of the rat juvenile hippocampus. This insulin-LTD may be due in part to internalization of the GluA2 subunit of the AMPA receptor (AMPAR) events that haven’t been studied in the mature rat hippocampus. In our studies, we used hippocampal preparations from juvenile (14 - 25 days) and mature (60 - 90 days) rats to assess insulin modulation of CA1 synaptic transmission and AMPAR trafficking and phosphorylation. Using field potential electrophysiology, we observed that insulin induced LTD in the juvenile hippocampus (as previously reported) in the presence and absence of phosphoinositide 3-kinase (PI3K) activity, but produced no significant long-term changes in the mature hippocampus in the presence of PI3K activity. Interestingly, during PI3K inhibition, insulin did produce LTD in the mature hippocampus. Additionally, insulin induced a long-term decrease in plasma membrane expression of the GluA2 and GluA1 subunits of the AMPAR in the juvenile, but not mature hippocampus. Furthermore, there was a long-term decrease in GluA1 phosphorylation at Serine 845 in the juvenile, but not mature hippocampus. These data reveal that insulin modulation of synaptic plasticity and AMPAR modulation within the hippocampus is age-dependent, suggesting that insulin-regulated behaviors may also show age-dependence. These findings are important largely due to the increased use of insulin as a therapeutic throughout the lifespan. Our data suggest that additional work should be done to determine how this use of insulin throughout different stages of life might affect synaptic function and development.
Highlights
Insulin, and its analogues, is widely used to treat endocrine disorders such as diabetes mellitus
The trafficking of α-amino-3-hydroxy-methyl-4isoxazolepropionic acid receptors (AMPARs) from the plasma membrane to internal compartments is a welldocumented event that plays a pivotal role in many forms of stimulus-induced long-term depression (LTD)
The measure of insulin signaling that we evaluated was p44/42, which is a mitogen-activated protein kinase (MAPK) that has been implicated in synaptic plasticity [27]-[29]
Summary
Its analogues, is widely used to treat endocrine disorders such as diabetes mellitus. In vitro field potential recordings have revealed that insulin induces long-term depression (LTD) in various regions of the hippocampus [8]-[11]. The whole cell recording studies have revealed that in mature animals, insulin produces LTD in region CA1 of the hippocampus [12]. GluA2 internalization is believed to be an underlying mechanism of insulin-LTD in juvenile animals [14]. It has been reported that insulin causes a decrease in the surface expression of the GluA2 subunit in hippocampal slices from juvenile rats [9] and in HEK293 cells [12], insulin-induced effects on GluA2 trafficking have not been investigated in mature rats. In addition to AMPAR subunit internalization, stimulus-LTD is associated with decreased phosphorylation of GluA1 at S845 (pGluA1S845) [14]. It has been shown that insulin induces phosphorylation of the GluA1 receptor at S830 [15], the effects of insulin on pGluA1S845 remain unpublished
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