Synaptic plasticity of inhibitory synapses onto medial olivocochlear efferent neurons

The descending auditory system modulates the ascending system at every level. The final descending, or efferent stage, is comprised of lateral olivocochlear (LOC) and medial olivocochlear (MOC) neurons. MOC somata in the ventral brainstem project axons to the cochlea to synapse onto outer hair cells (OHC), inhibiting OHC-mediated cochlear amplification. MOC suppression of OHC function is implicated in cochlear gain control with changing sound intensity, detection of salient stimuli, attention, and protection against acoustic trauma. Thus, sound excites MOC neurons to provide negative feedback of the cochlea. Sound also inhibits MOC neurons via medial nucleus of the trapezoid body (MNTB) neurons. However, MNTB-MOC synapses exhibit short-term depression, suggesting reduced MNTB-MOC inhibition during sustained stimuli. Further, due to high rates of both baseline and sound-evoked activity in MNTB neurons in vivo, MNTB-MOC synapses may be tonically depressed. To probe this, we characterized short-term plasticity of MNTB-MOC synapses in mouse brain slices. We mimicked in vivo-like temperature and extracellular calcium conditions, and in vivo-like activity patterns of fast synaptic activation rates, sustained activation, and prior tonic activity. Synaptic depression was sensitive to extracellular calcium concentration and temperature. During rapid MNTB axon stimulation, post-synaptic currents (PSCs) in MOC neurons summated but with concurrent depression, resulting in smaller, sustained currents, suggesting tonic inhibition of MOC neurons during rapid circuit activity. Low levels of baseline MNTB activity did not significantly reduce responses to subsequent rapid activity that mimics sound stimulation, indicating that, in vivo, MNTB inhibition of MOC neurons persists despite tonic synaptic depression.

Modelling novelty detection in the thalamocortical loop

In complex natural environments, sensory systems are constantly exposed to a large stream of inputs. Novel or rare stimuli, which are often associated with behaviorally important events, are typically processed differently than the steady sensory background, which has less relevance. Neural signatures of such differential processing, commonly referred to as novelty detection, have been identified on the level of EEG recordings as mismatch negativity and the level of single neurons as stimulus-specific adaptation. Here, we propose a multi-scale recurrent network with synaptic depression to explain how novelty detection can arise in the whisker-related part of the somatosensory thalamocortical loop. The architecture and dynamics of the model presume that neurons in cortical layer 6 adapt, via synaptic depression, specifically to a frequently presented stimulus, resulting in reduced population activity in the corresponding cortical column when compared with the population activity evoked by a rare stimulus. This difference in population activity is then projected from the cortex to the thalamus and amplified through the interaction between neurons of the primary and reticular nuclei of the thalamus, resulting in spindle-like, rhythmic oscillations. These differentially activated thalamic oscillations are forwarded to cortical layer 4 as a late secondary response that is specific to rare stimuli that violate a particular stimulus pattern. Model results show a strong analogy between this late single neuron activity and EEG-based mismatch negativity in terms of their common sensitivity to presentation context and timescales of response latency, as observed experimentally. Our results indicate that adaptation in L6 can establish the thalamocortical dynamics that produce signatures of SSA and MMN and suggest a mechanistic model of novelty detection that could generalize to other sensory modalities.

β-amyloid-driven synaptic depression requires PDZ protein interaction at AMPA-receptor subunit GluA3

Soluble oligomeric amyloid-β (Aβ) is a prime suspect to cause cognitive deficits in Alzheimer's disease and weakens synapses by removing AMPA-type glutamate receptors (AMPARs). We show that synapses of CA1 pyramidal neurons become vulnerable to Aβ when they express AMPAR subunit GluA3. We found that Aβ-oligomers reduce the levels of GluA3 immobilized at spines, indicating they deplete GluA3-containing AMPARs from synapses. These Aβ-driven effects critically depended on the PDZ-binding motif of GluA3. When GluA3 was expressed with a single amino acid mutation in its PDZ-binding motif that prevents GRIP binding, it did not end up at spines and Aβ failed to trigger synaptic depression. GluA3 with a different point mutation in the PDZ-motif that leaves GRIP-binding intact but prevents its endocytosis, was present at spines in normal amounts but was fully resistant to effects of Aβ. Our data indicate that Aβ-mediated synaptic depression requires the removal of GluA3 from synapses. We propose that GRIP-detachment from GluA3 is a critical early step in the cascade of events through which Aβ accumulation causes a loss of synapse.

Aberrant Synaptic PTEN in Symptomatic Alzheimer’s Patients May Link Synaptic Depression to Network Failure

In Alzheimer’s disease (AD), Amyloid β (Aβ) impairs synaptic function by inhibiting long-term potentiation (LTP), and by facilitating long-term depression (LTD). There is now evidence from AD models that Aβ provokes this shift toward synaptic depression by triggering the access to and accumulation of PTEN in the postsynaptic terminal of hippocampal neurons. Here we quantified the PTEN in 196,138 individual excitatory dentate gyrus synapses from AD patients at different stages of the disease and from controls with no neuropathological findings. We detected a gradual increase of synaptic PTEN in AD brains as the disease progresses, in conjunction with a significant decrease in synaptic density. The synapses that remain in symptomatic AD patients are more likely to be smaller and exhibit fewer AMPA receptors (AMPARs). Hence, a high Aβ load appears to strongly compromise human hippocampal synapses, as reflected by an increase in PTEN, inducing a loss of AMPARs that may eventually provoke synaptic failure and loss.

Dopaminergic Neuromodulation of Spike Timing Dependent Plasticity in Mature Adult Rodent and Human Cortical Neurons

Synapses in the cerebral cortex constantly change and this dynamic property regulated by the action of neuromodulators such as dopamine (DA), is essential for reward learning and memory. DA modulates spike-timing-dependent plasticity (STDP), a cellular model of learning and memory, in juvenile rodent cortical neurons. However, it is unknown whether this neuromodulation also occurs at excitatory synapses of cortical neurons in mature adult mice or in humans. Cortical layer V pyramidal neurons were recorded with whole cell patch clamp electrophysiology and an extracellular stimulating electrode was used to induce STDP. DA was either bath-applied or optogenetically released in slices from mice. Classical STDP induction protocols triggered non-hebbian excitatory synaptic depression in the mouse or no plasticity at human cortical synapses. DA reverted long term synaptic depression to baseline in mouse via dopamine 2 type receptors or elicited long term synaptic potentiation in human cortical synapses. Furthermore, when DA was applied during an STDP protocol it depressed presynaptic inhibition in the mouse but not in the human cortex. Thus, DA modulates excitatory synaptic plasticity differently in human vs. mouse cortex. The data strengthens the importance of DA in gating cognition in humans, and may inform on therapeutic interventions to recover brain function from diseases.

Input-selective adenosine A1 receptor-mediated synaptic depression of excitatory transmission in dorsal striatum

The medial (DMS) and lateral (DLS) dorsal striatum differentially drive goal-directed and habitual/compulsive behaviors, respectively, and are implicated in a variety of neuropsychiatric disorders. These subregions receive distinct inputs from cortical and thalamic regions which uniquely determine dorsal striatal activity and function. Adenosine A1 receptors (A1Rs) are prolific within striatum and regulate excitatory glutamate transmission. Thus, A1Rs may have regionally-specific effects on neuroadaptive processes which may ultimately influence striatally-mediated behaviors. The occurrence of A1R-driven plasticity at specific excitatory inputs to dorsal striatum is currently unknown. To better understand how A1Rs may influence these behaviors, we first sought to understand how A1Rs modulate these distinct inputs. We evaluated A1R-mediated inhibition of cortico- and thalamostriatal transmission using in vitro whole-cell, patch clamp slice electrophysiology recordings in medium spiny neurons from both the DLS and DMS of C57BL/6J mice in conjunction with optogenetic approaches. In addition, conditional A1R KO mice lacking A1Rs at specific striatal inputs to DMS and DLS were generated to directly determine the role of these presynaptic A1Rs on the measured electrophysiological responses. Activation of presynaptic A1Rs produced significant and prolonged synaptic depression (A1R-SD) of excitatory transmission in the both the DLS and DMS of male and female animals. Our findings indicate that A1R-SD at corticostriatal and thalamostriatal inputs to DLS can be additive and that A1R-SD in DMS occurs primarily at thalamostriatal inputs. These findings advance the field’s understanding of the functional roles of A1Rs in striatum and implicate their potential contribution to neuropsychiatric diseases.