mGluR5 Positive Allosteric Modulators Facilitate both Hippocampal LTP and LTD and Enhance Spatial Learning

Abstract

Highly selective positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGluR5) have emerged as a potential approach to treat positive symptoms associated with schizophrenia. mGluR5 plays an important role in both long term potentiation (LTP) and long term depression (LTD), suggesting that mGluR5 PAMs may also have utility in improving impaired cognitive function. However, if mGluR5 PAMs shift the balance of LTP and LTD or induce a state in which afferent activity induces lasting changes in synaptic function that are not appropriate for a given pattern of activity, this could disrupt rather than enhance cognitive function. We determined the effect of selective mGluR5 PAMs on induction of LTP and LTD at the Schaffer collateral – CA1 synapse in the hippocampus. mGluR5-selective PAMs significantly enhanced threshold theta burst stimulation (TBS)-induced LTP. In addition, mGluR5 PAMs enhanced both DHPG-induced LTD and LTD induced by delivery of paired-pulse low frequency stimulation. Selective potentiation of mGluR5 had no effect on LTP induced by suprathreshold TBS or saturated LTP. The finding that potentiation of mGluR5-mediated responses to stimulation of glutamatergic afferents enhances both LTP and LTD supports the hypothesis that activation of mGluR5 by endogenous glutamate contributes to both forms of plasticity. Furthermore, two systemically active mGluR5 PAMs enhanced performance in the Morris water maze, a measure of hippocampus-dependent spatial learning. Discovery of small molecules that enhance both LTP and LTD in an activity-appropriate manner demonstrates a unique action on synaptic plasticity that may provide a novel approach for treatment of impaired cognitive function.

proBDNF and p75NTR Control Excitability and Persistent Firing of Cortical Pyramidal Neurons

“…Two previous studies have shown that p75NTR Ϫ/Ϫ mice display improved performance in tests of spatial memory and those authors proposed that p75NTR acts as a negative regulator of hippocampal function (Greferath et al, 2000;Barrett et al, 2010). Cholinergic neurons express high levels of p75NTR and germline deletion of p75NTR has been reported to increase cholinergic innervation of the hippocampus (Yeo et al, 1997).…”

“…We have previously reported that PIP2 functions as a potent suppressor of TRPC4/5 in the EC and proposed that a phospholipase C-dependent reduction in PIP2 level was a prerequisite for the emergence of persistent firing (Ayala et al, 2009;Zhang et al, 2011). Consistent with these previous results, we show here that LY294002, which blocks the conversion of PIP2 to PIP3, completely blocks CCh-induced persistent firing.…”

Selective Remediation of Reversal Learning Deficits in the Neurodevelopmental MAM Model of Schizophrenia by a Novel mGlu5 Positive Allosteric Modulator

“…mGlu5 receptors are expressed in key brain regions for cognition, including hippocampus, amygdala, striatum and prefrontal cortex (Shigemoto et al, 1993;Romano et al, 1995). Accordingly, modulation of mGlu5 can alter a wide range of cognitive functions in rodents (Kinney et al, 2003;Homayoun et al, 2004;Manahan-Vaughan and Braunewell, 2005;Semenova and Markou, 2007;Ayala et al, 2009;Xu et al, 2009;see Homayoun and Moghaddam, 2010). In addition, studies with the mGlu5 PAM ADX47273 have reported both antipsychotic and procognitive effects, such as increased novel object recognition and reduced impulsivity in the five-choice serial reaction time test in rats (Liu et al, 2008), but no studies are yet reported in neurodevelopmental rodent models of schizophrenia.…”

Blockade of mGluR5 in the nucleus accumbens shell but not core attenuates heroin seeking behavior in rats

“…For example, the potentiation of mGluR5 function has been demonstrated to mediate various forms of synaptic plasticity [5] . The antagonism of mGluR5 by MPEP attenuated heroinseeking behavior in the present study, which is consistent with the previous data that systemic administration of MPEP attenuates the reinstatement of various classes of other abused drugs in preclinical models [5,9,10,14] . Moreover, another antagonist of mGluR5 also attenuates opiate self-administration and opiate-seeking behavior in mice [17] .…”

“…The pre-clinical literature indicates that longterm drug-induced alterations in glutamatergic transmission within the NAc may underlie relapse to drug-seeking behavior following the re-exposure to drugs and drugassociated stimuli during abstinence of the drug [3,4] . Type 5 metabotropic glutamate receptor (mGluR5) as a postsynaptic element is abundantly present throughout in the NAc, where it is positively coupled to NMDA receptor function and mediates various forms of synaptic plasticity [5,6] . The deletion of mGluR5 results in marked deficits in responding to the reinforcing and locomotor stimulating effects of cocaine [7] .…”