Conditional mGluR5 knockout in glutamatergic pathways disrupts the development of excitatory synaptic transmission onto mouse MNTB neurons

Metabotropic glutamate receptor 5 (mGluR5) plays a pivotal role in neurodevelopment. Here, we investigated the consequences of mGluR5 loss-of-function on the development of glutamatergic transmission onto the medial nucleus of the trapezoid body (MNTB). Using the Cre-loxP system, we generated a conditional knockout (KO) mouse line in which mGluR5 expression was selectively eliminated in vesicular glutamate transporter 2 (VGluT2)-expressing glutamatergic pathways, including the calyx of Held synapse innervating MNTB neurons. Whole cell patch-clamp recordings from mice of either sex at <i>postnatal days 30</i>-<i>38</i> were used to compare the excitatory synaptic properties of MNTB neurons between KO mice and wild-type controls. Upon afferent stimulation of the trapezoid body, MNTB neurons exhibited two distinct types of evoked EPSCs (eEPSCs): large calyceal all-or-none and smaller non-calyceal responses. In mGluR5 KO mice, there was a significant increase in the proportion of neurons exhibiting non-calyceal eEPSCs. The calyceal all-or-none eEPSCs showed significantly prolonged latency, along with slower kinetics in both eEPSCs and asynchronous EPSCs. Analysis of short-term synaptic plasticity of the non-calyceal eEPSCs revealed an increased paired-pulse ratio in mGluR5 KO mice. In addition, membrane capacitance was significantly reduced, consistent with a smaller somatic area in mGluR5 KO mice. These results suggest that mGluR5 plays a critical role in shaping the excitatory synaptic properties necessary for fast temporal processing in the MNTB.<b>NEW & NOTEWORTHY</b> Metabotropic glutamate receptor 5 (mGluR5) is known to play critical roles in neurodevelopment, but its specific contribution to auditory circuit formation has remained unknown. Using a conditional mGluR5 knockout mouse model, we show that a major glutamatergic pathway in the auditory brainstem is impaired, particularly in synaptic timing, and is accompanied by a reduced somatic area of the postsynaptic neurons. These findings highlight a pivotal role for mGluR5 in shaping auditory brainstem circuitry.