Hippocampal Metaplasticity Is Required for the Formation of Temporal Associative Memories

Abstract

Metaplasticity regulates the threshold for modification of synaptic strength and is an important regulator of learning rules; however, it is not known whether these cellular mechanisms for homeostatic regulation of synapses contribute to particular forms of learning. Conditional ablation of mGluR5 in CA1 pyramidal neurons resulted in the inability of low-frequency trains of afferent activation to prime synapses for subsequent theta burst potentiation. Priming-induced metaplasticity requires mGluR5-mediated mobilization of endocannabinoids during the priming train to induce long-term depression of inhibition (I-LTD). Mice lacking priming-induced plasticity had no deficit in spatial reference memory tasks, but were impaired in an associative task with a temporal component. Conversely, enhancing endocannabinoid signaling facilitated temporal associative memory acquisition and, after training animals in these tasks, ex vivo I-LTD was partially occluded and theta burst LTP was enhanced. Together, these results suggest a link between metaplasticity mechanisms in the hippocampus and the formation of temporal associative memories.

Cholinergic Neurons of the Medial Septum Are Crucial for Sensorimotor Gating

“…We generated the three conditional mouse lines by crossing existing and well characterized mouse lines. Briefly, floxed mGluR5 mice (Xu et al, 2009(Xu et al, , 2014Lee et al, 2015) were crossed with three different Cre lines (1) empty spiracles homeobox 1Ј (EMX)-Cre (Gorski et al, 2002;Lee et al, 2015), (2) PV-positive-Cre (Hippenmeyer et al, 2005;Lee et al, 2015), and (3) ChAT-Cre (Rossi et al, 2011) to delete mGluR5 in glutamatergic, PV-positive GABAergic, and cholinergic neurons, respectively. For each mouse line, immunohistochemical labeling studies were performed to ensure that the KO of mGluR5 was effective.…”

“…The floxed mGluR5 mouse line (generous gift from Dr. A. Contractor, Northwesten University; Xu et al, 2009Xu et al, , 2014Lee et al, 2015) were crossed with EMX1-cre (stock 005628, The Jackson Laboratory; Gorski et al, 2002), parvalbumin (PV)-cre (stock 008069, The Jackson Laboratory; Hippenmeyer et al, 2005), and choline acetyl transferase (ChAT)-cre (stock 006410, The Jackson Laboratory; Rossi et al, 2011) mouse lines to delete mGluR5 in glutamatergic, PV-positive GABAergic, and cholinergic neurons, respectively. The ChAT-cre mouse line (stock 006410, The Jackson Laboratory) was used for DREADD-mediated manipulation of cholinergic neurons.…”

Complete Disruption of the Kainate Receptor Gene Family Results in Corticostriatal Dysfunction in Mice

“…Parasagittal or coronal slices containing the dorsal striatum or horizontal hippocampal slices were prepared using techniques modified from those previously described (Xu et al, 2014). Individual slices were transferred to a recording chamber and visualized.…”

Synaptic functions of endocannabinoid signaling in health and disease

“…Changes in the inducibility of LTP, a phenomenon known as metaplasticity, could play an important role in learning and memory. Remarkably, eCB-dependent metaplasticity initially described in vitro (Chevaleyre and Castillo, 2004) has recently been reported in vivo and could contribute to the formation of temporal associative memories (Xu et al, 2014). In addition, eCB-iLTD is involved the potentiation of excitatory postsynaptic potential (EPSP)-spike coupling (E-S coupling) (Chevaleyre and Castillo, 2003).…”