Summary Controlled cortical impact injury was used to examine relationships between focal posttraumatic cortical damage and mossy fiber sprouting (MFS) in the dentate gyrus in three mouse strains. Posttraumatic MFS was more robust when cortical injury impinged upon the hippocampus, versus contusions restricted to neocortex, and was qualitatively similar among CD-1, C57BL/6, and FVB/N background strains. Impact parameters influencing injury severity may be critical in reproducing epilepsy-related changes in neurotrauma models.

A variety of metabolic disorders, including complications experienced by diabetic patients, have been linked to altered neural activity in the dorsal vagal complex. This study tested the hypothesis that augmentation of N-Methyl-D-Aspartate (NMDA) receptor-mediated responses in the vagal complex contributes to increased glutamate release in the dorsal motor nucleus of the vagus nerve (DMV) in mice with streptozotocin-induced chronic hyperglycemia (i.e., hyperglycemic mice), a model of type 1 diabetes. Antagonism of NMDA receptors with AP-5 (100 μM) suppressed sEPSC frequency in vagal motor neurons recorded in vitro, confirming that constitutively active NMDA receptors regulate glutamate release in the DMV. There was a greater relative effect of NMDA receptor antagonism in hyperglycemic mice, suggesting that augmented NMDA effects occur in neurons presynaptic to the DMV. Effects of NMDA receptor blockade on mEPSC frequency were equivalent in control and diabetic mice, suggesting that differential effects on glutamate release were due to altered NMDA function in the soma-dendritic membrane of intact afferent neurons. Application of NMDA (300 μM) resulted in greater inward current and current density in NTS neurons recorded from hyperglycemic than control mice, particularly in glutamatergic NTS neurons identified by single-cell RT-PCR for VGLUT2. Overall expression of NR1 protein and message in the dorsal vagal complex were not different between the two groups. Enhanced postsynaptic NMDA responsiveness of glutamatergic NTS neurons is consistent with tonically-increased glutamate release in the DMV in mice with chronic hyperglycemia. Functional augmentation of NMDA-mediated responses may serve as a physiological counter-regulatory mechanism to control pathological disturbances of homeostatic autonomic function in type 1 diabetes.

Bach EC, Smith BN. Presynaptic NMDA receptor-mediated modulation of excitatory neurotransmission in the mouse dorsal motor nucleus of the vagus. J Neurophysiol 108: 1484 -1491, 2012. First published June 13, 2012 doi:10.1152/jn.01036.2011.-Activity of neurons in the dorsal motor nucleus of the vagus nerve (DMV) is closely regulated by synaptic input, and regulation of that input by glutamate receptors on presynaptic terminals has been proposed. Presynaptic N-methyl-D-aspartic acid (NMDA) receptors have been identified in a number of brain regions and act to modulate neurotransmitter release, but functional presynaptic NMDA receptors have not been adequately studied in the DMV. This study identified the presence and physiological function of presynaptic NMDA receptors on synaptic input to DMV neurons. Whole-cell patch-clamp recordings from DMV neurons in acute slices from mice revealed prevalent miniature excitatory postsynaptic currents, which were significantly increased in frequency, but not amplitude, by application of NMDA. Antagonism of NMDA receptors with DL-2-amino-5-phosphonopentanoic acid (100 M) resulted in a decrease in miniature excitatory postsynaptic current frequency and an increase in the paired pulse ratio of responses following afferent stimulation. No consistent effects of presynaptic NMDA receptor modulation were observed on GABAergic inputs. These results suggest that presynaptic NMDA receptors are present in the dorsal vagal complex and function to facilitate the release of glutamate, preferentially onto DMV neurons tonically, with little effect on GABA release. This type of presynaptic modulation represents a potentially novel form of glutamate regulation in the DMV, which may function to regulate glutamate-induced activity of central parasympathetic circuits.

Before the onset of hearing, cochlea-generated patterns of spontaneous spike activity drive the maturation of central auditory circuits. In the glycinergic sound localization pathway from the medial nucleus of the trapezoid body (MNTB) to the lateral superior olive (LSO) this spontaneous activity guides the strengthening and silencing of synapses which underlies tonotopic map refinement. However, the mechanisms by which patterned activity regulates synaptic refinement in the MNTB-LSO pathway are still poorly understood. To address this question, we recorded from LSO neurons in slices from prehearing mice while stimulating MNTB afferents with stimulation patterns that mimicked those present in vivo. We found that these semi-natural stimulation patterns reliably elicited a novel form of long-term potentiation (LTP) of MNTB-LSO synapses. Stimulation patterns that lacked the characteristic high-frequency (200 Hz) component of prehearing spike activity failed to elicit potentiation. LTP was calcium dependent, required the activation of both g-protein coupled GABAB and metabotropic glutamate receptors and involved an increase in postsynaptic glycine receptor-mediated currents. Our results provide a possible mechanism linking spontaneous spike bursts to tonotopic map refinement and further highlight the importance of the co-release of GABA and glutamate from immature glycinergic MNTB terminals.

During development GABA and glycine synapses are initially excitatory before they gradually become inhibitory. This transition is due to a developmental increase in the activity of neuronal potassium-chloride cotransporter 2 (KCC2), which shifts the chloride equilibrium potential (ECl) to values more negative than the resting membrane potential. While the role of early GABA and glycine depolarizations in neuronal development has become increasingly clear, the role of the transition to hyperpolarization in synapse maturation and circuit refinement has remained an open question. Here we investigated this question by examining the maturation and developmental refinement of GABA/glycinergic and glutamatergic synapses in the lateral superior olive (LSO), a binaural auditory brain stem nucleus, in KCC2-knockdown mice, in which GABA and glycine remain depolarizing. We found that many key events in the development of synaptic inputs to the LSO, such as changes in neurotransmitter phenotype, strengthening and elimination of GABA/glycinergic connection, and maturation of glutamatergic synapses, occur undisturbed in KCC2-knockdown mice compared with wild-type mice. These results indicate that maturation of inhibitory and excitatory synapses in the LSO is independent of the GABA and glycine depolarization-to-hyperpolarization transition.