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Neuroligins are postsynaptic cell-adhesion molecules implicated in autism and other neuropsychiatric disorders. Despite extensive work, the role of neuroligins in synapse function and plasticity, especially N -methyl- d -aspartate (NMDA) receptor (NMDAR)-dependent long-term potentiation (LTP), remains unclear. To establish which synaptic functions unequivocally require neuroligins, we analyzed single and triple conditional knockout (cKO) mice for all three major neuroligin isoforms (NL1–NL3). We inactivated neuroligins by stereotactic viral expression of Cre-recombinase in hippocampal CA1 region pyramidal neurons at postnatal day 0 (P0) or day 21 (P21) and measured synaptic function, synaptic plasticity and spine numbers in acute hippocampal slices 2–3 weeks later. Surprisingly, we find that ablation of neuroligins in newborn or juvenile mice only modestly impaired basal synaptic function in hippocampus and caused no alteration in postsynaptic spine numbers. However, triple cKO of NL1–NL3 or single cKO of NL1 impaired NMDAR-mediated excitatory postsynaptic currents and abolished NMDAR-dependent LTP. Strikingly, the NL1 cKO also abolished LTP elicited by activation of L-type Ca 2+ -channels during blockade of NMDARs. These findings demonstrate that neuroligins are generally not essential for synapse formation in CA1 pyramidal neurons but shape synaptic properties and that NL1 specifically is required for LTP induced by postsynaptic Ca 2+ -elevations, a function which may contribute to the pathophysiological role of neuroligins in brain disorders.

The biochemical composition of the postsynaptic membrane and the structure of dendritic spines may be rapidly modulated by synaptic activity. Here we review these findings, discuss their implications for long-term potentiation (LTP) and long-term depression (LTD) and propose a model of sequentially occurring expression mechanisms.

The striatum and its ventral extension, the nucleus accumbens, are involved in behaviors as diverse as motor planning, drug seeking, and learning. Invariably, these striatally mediated behaviors depend on intact dopaminergic innervation. However, the mechanisms by which dopamine modulates neuronal function in the striatum and nucleus accumbens have been difficult to elucidate. Recent electrophysiological studies have revealed that dopamine alters both voltage-dependent conductances and synaptic transmission, resulting in state-dependent modulation of target cells. These studies make clear predictions about how dopamine, particularly via D1 receptor activation, should alter the responsiveness of striatal neurons to extrinsic excitatory synaptic activity.

Synaptic plasticity in the mesolimbic dopamine (DA) system is thought to contribute to the neural adaptations that mediate behavioral sensitization, a model for core aspects of addiction. Recently, it has been demonstrated that multiple classes of drugs of abuse, as well as acute stress, enhance strength at excitatory synapses on midbrain DA neurons. Here, we show that both the cocaine- and stress-induced synaptic enhancement involves an up-regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. This enhancement requires the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit GluRA as evidenced by its absence in mice lacking this subunit. The cocaine-elicited, but not the stress-elicited, synaptic potentiation in DA neurons was blocked by a D1-like receptor antagonist, indicating that the in vivo triggering mechanisms differ for these forms of experience-dependent synaptic modification. Surprisingly, behavioral sensitization to cocaine was elicited in GluRA(-/-) mice, indicating that potentiation of excitatory synaptic transmission in DA neurons is not necessary for this form of behavioral plasticity. However, GluRA(-/-) mice did not exhibit a conditioned locomotor response when placed in a context previously paired with cocaine, nor did they exhibit conditioned place preference in response to cocaine. We suggest that the drug-induced enhancement of excitatory synaptic transmission in midbrain DA neurons, although not required for behavioral sensitization per se, may contribute to the attribution of incentive value to drug-associated cues.

Although kainate receptor activation has been known to evoke epileptiform activity, little is known about the role of kainate receptors in synaptic transmission. Here we report that kainate (KA) receptors are present on interneurons and, when activated, cause a large increase in the frequency of spontaneous inhibitory postsynaptic currents (IPSCs) driven by action potentials. Stimulation of excitatory afferents generates a pharmacologically identifiable synaptic current mediated by KA receptors in interneurons. This synaptic current is similar to that mediated by AMPA receptors in its response to short stimulus trains, current–voltage relations and coefficient of variation, but it is much smaller in peak amplitude and much slower. KA application also considerably depresses evoked IPSCs. This depression seems to be in large part an indirect consequence of the repetitive firing evoked by the activation of the interneuronal somatic/dendritic KA receptors.

Overactivity of the dopaminergic system in the brain is considered to be a contributing factor to the development and symptomatology of schizophrenia. Therefore, the GABAergic control of dopamine functions was assessed by disrupting the gene encoding the α3 subunit of the GABA A receptor. α3 knockout (α3KO) mice exhibited neither an obvious developmental defect nor apparent morphological brain abnormalities, and there was no evidence for compensatory up-regulation of other major GABA A -receptor subunits. Anxiety-related behavior in the elevated-plus-maze test was undisturbed, and the anxiolytic-like effect of diazepam, which is mediated by α2-containing GABA A receptors, was preserved. As a result of the loss of α3 GABA A receptors, the GABA-induced whole-cell current recorded from midbrain dopamine neurons was significantly reduced. Spontaneous locomotor activity was slightly elevated in α3KO mice. Most notably, prepulse inhibition of the acoustic startle reflex was markedly attenuated in the α3KO mice, pointing to a deficit in sensorimotor information processing. This deficit was completely normalized by treatment with the antipsychotic D2-receptor antagonist haloperidol. The amphetamine-induced hyperlocomotion was not altered in α3KO mice compared with WT mice. These results suggest that the absence of α3-subunit-containing GABA A receptors induces a hyperdopaminergic phenotype, including a severe deficit in sensorimotor gating, a common feature among psychiatric conditions, including schizophrenia. Hence, agonists acting at α3-containing GABA A receptors may constitute an avenue for an effective treatment of sensorimotor-gating deficits in various psychiatric conditions. haloperidol sensorimotor gating

Glutamate, the neurotransmitter at most excitatory synapses in the brain, activates a variety of receptor subtypes that can broadly be divided into ionotropic (ligand-gated ion channels) and metabotropic (G-protein-coupled) receptors. Ionotropic receptors mediate fast excitatory synaptic transmission, and based on pharmacological and molecular biological studies are divided into NMDA and non-NMDA subtypes. The non-NMDA receptor group is further divided into AMPA and kainate subtypes. Virtually all fast excitatory postsynaptic currents studied so far in the central nervous system are mediated by the AMPA and NMDA subtypes of receptors. Surprisingly, despite extensive analysis of their structure, biophysical properties and anatomical distribution, a synaptic role for kainate receptors in the brain has not been found. Here we report that repetitive activation of the hippocampal mossy fibre pathway, which is associated with high-affinity kainate binding and many of the kainate receptor subtypes, generates a slow excitatory synaptic current with all of the properties expected of a kainate receptor. This activity-dependent synaptic current greatly augments the excitatory drive of CA3 pyramidal cells.

IN mammalian development, the refinement of topographical projections from the thalamus to the cortex is thought to arise through an activity-dependent process in which thalamic axons compete for cortical targets 1,2 . In support of this view, if activity is altered during a critical period in early development, normal connectivity is disrupted 1,2 . It has been proposed that synaptic connections are strengthened during development by correlated pre- and postsynaptic activity 3,4 , and a likely mechanism for this process would be N -methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation (LTP) 5,6 . However, the evidence that LTP is involved in normal development remains inconclusive. We have examined LTP in the thalamocortical synapses that form whisker barrels in rat somatosensory cortex (SI). We report here that the period during which LTP can be induced matches closely the critical period during which the barrels can be modified by sensory perturbations. Moreover, the loss of susceptibility to LTP with age is accompanied by a decrease in NMDA receptor-mediated synaptic currents. These findings provide compelling evidence that LTP is important for the development of cortical circuitry.

▪ Abstract  Activity-dependent changes in synaptic function are believed to underlie the formation of memories. Two prominent examples are long-term potentiation (LTP) and long-term depression (LTD), whose mechanisms have been the subject of considerable scrutiny over the past few decades. Here we review the growing literature that supports a critical role for AMPA receptor trafficking in LTP and LTD, focusing on the roles proposed for specific AMPA receptor subunits and their interacting proteins. While much work remains to understand the molecular basis for synaptic plasticity, recent results on AMPA receptor trafficking provide a clear conceptual framework for future studies.

Long-term potentiation of synaptic transmission in the hippocampus is the leading experimental model for the synaptic changes that may underlie learning and memory. This review presents a current understanding of the molecular mechanisms of this long-lasting increase in synaptic strength and describes a simple model that unifies much of the data that previously were viewed as contradictory.