Ketamine has been shown to reduce depression and suicidality in individuals resistant to treatment by other drugs. Exactly how ketamine works is not known. Here, I propose a new hypothesis that involves synaptic and circuit plasticity and may lead to enhanced efficacy in treating depression as well as other conditions.

Spontaneously occurring miniature excitatory postsynaptic currents (mEPSCs) are fundamental electrophysiological events produced by quantal vesicular transmitter release at synapses. Their analysis can provide important information regarding pre- and postsynaptic function. However, the small signal relative to recording noise requires expertise and considerable time for their identification. Furthermore, many mEPSCs smaller than similar to 8 pA are not well resolved (e.g., those produced at distant synapses or synapses with few receptor channels). Here, we describe an automated approach to detect mEPSCs using a machine learning-based tool. This method, which can be easily generalized to other one- dimensional signals, eliminates inter- observer bias, provides an estimate of its sensitivity and specificity and permits reliable detection of small (e.g., 5 pA) spontaneous unitary synaptic events.

Beta-amyloid (A beta) depresses excitatory synapses by a poorly understood mechanism requiring NMDA receptor (NMDAR) function. Here, we show that increased PSD-95, a major synaptic scaffolding molecule, blocks the effects of A beta on synapses. The protective effect persists in tissue lacking the AMPA receptor subunit GluA1, which prevents the confounding synaptic potentiation by increased PSD-95. A beta modifies the conformation of the NMDAR C-terminal domain (CTD) and its interaction with protein phosphatase 1 (PP1), producing synaptic weakening. Higher endogenous levels or overexpression of PSD-95 block A beta-induced effects on the NMDAR CTD conformation, its interaction with PP1, and synaptic weakening. Our results indicate that increased PSD-95 protects synapses from A beta toxicity, suggesting that low levels of synaptic PSD-95 may be a molecular sign indicating synapse vulnerability to A beta. Importantly, pharmacological inhibition of its depalmitoylation increases PSD-95 at synapses and rescues deficits caused by A beta, possibly opening a therapeutic avenue against Alzheimer's disease.

There is hope that genomic information will assist prediction, treatment, and understanding of Alzheimer’s disease (AD). Here, using exome data from ∼10,000 individuals, we explore machine learning neural network (NN) methods to estimate the impact of SNPs (i.e., genetic variants) on AD risk. We develop an NN-based method (netSNP) that identifies hundreds of novel potentially protective or at-risk AD-associated SNPs (along with an effect measure); the majority with frequency under 0.01. For case individuals, the number of “protective” (or “at-risk”) netSNP-identified SNPs in their genome correlates positively (or inversely) with their age of AD diagnosis and inversely (or positively) with autopsy neuropathology. The effect measure increases correlations. Simulations suggest our results are not due to genetic linkage, overfitting, or bias introduced by netSNP. These findings suggest that netSNP can identify SNPs associated with AD pathophysiology that may assist with the diagnosis and mechanistic understanding of the disease.

Which neural circuits undergo synaptic changes when an animal learns? Although it is widely accepted that changes in synaptic strength underlie many forms of learning and memory, it remains challenging to connect changes in synaptic strength at specific neural pathways to specific behaviors and memories. Here we introduce SYNPLA (synaptic proximity ligation assay), a synapse-specific, high-throughput, and potentially brain-wide method capable of detecting circuit-specific learning-induced synaptic plasticity.

Slow response to the standard treatment for depression increases suffering and risk of suicide. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, can rapidly alleviate depressive symptoms and reduce suicidality, possibly by decreasing hyperactivity in the lateral habenula (LHb) brain nucleus. Here we find that in a rat model of human depression, opioid antagonists abolish the ability of ketamine to reduce the depression-like behavioral and LHb hyperactive cellular phenotypes. However, activation of opiate receptors alone is not sufficient to produce ketamine-like effects, nor does ketamine mimic the hedonic effects of an opiate, indicating that the opioid system does not mediate the actions of ketamine but rather is permissive. Thus, ketamine does not act as an opiate but its effects require both NMDA and opiate receptor signaling, suggesting that interactions between these two neurotransmitter systems are necessary to achieve an antidepressant effect.

Ketamine can rapidly alleviate depressive symptoms and reduce suicidality, possibly by decreasing hyperactivity in the lateral habenula (LHb). Unlike other drugs currently used for treatment of depression, ketamine displays high affinity for, and inhibits, the NMDA receptor (NMDAR). However, other NMDAR antagonists don’t produce an antidepressant response and ketamine also binds to a variety of other targets, including the mu-opioid receptor. Here we test if the effects of ketamine are mediated by the opioid system, using behavioral and cellular assays

We recently demonstrated that NMDA receptors (NMDARs) are capable of ion-flux independent signaling through conformational change in the NMDAR intracellular domain resulting in long-term depression of synaptic transmission (LTD). Here we show that PSD-95 overexpression blocks agonist induced conformational movement in the NMDAR intracellular domain as well as LTD that is NMDAR-dependent and ion-flux independent. Interestingly, previous studies indicate that overexpressed PSD-95 does not block NMDAR-dependent LTD. These data support a model where ion-flux independent LTD is predominant in young animals, which have synapses with low amounts of PSD-95, whereas only ion flux dependent LTD occurs at more mature synapses, which have more PSD-95 that would block ion-flux independent LTD. These results may reconcile different findings regarding ion-flux independent LTD.

We agree with Hashimoto (1) that the molecular mechanisms underlying the psychiatric properties of ( R , S )-ketamine remain active areas of investigation. Racemic ketamine as well as esketamine [( S )-ketamine] are potent N -methyl-d-aspartate receptor (NMDAR) antagonists and have displayed acute antidepressant and antisuicidal effects in multiple clinical studies (2, 3). However, these compounds display activity, albeit with lower affinity, on a number of receptors, including μ-opioid receptors (MORs), complicating the issue of mechanism of action. Clinical studies arguing for (4) and against (5) a role for MORs … [↵][1]1To whom correspondence may be addressed. Email: meklein{at}ucsd.edu. [1]: #xref-corresp-1-1

We agree with Hashimoto (1) that the molecular mechanisms underlying the psychiatric properties of ( R , S )-ketamine remain active areas of investigation. Racemic ketamine as well as esketamine [( S )-ketamine] are potent N -methyl-d-aspartate receptor (NMDAR) antagonists and have displayed acute antidepressant and antisuicidal effects in multiple clinical studies (2, 3). However, these compounds display activity, albeit with lower affinity, on a number of receptors, including μ-opioid receptors (MORs), complicating the issue of mechanism of action. Clinical studies arguing for (4) and against (5) a role for MORs … \n\n[↵][1]1To whom correspondence may be addressed. Email: meklein{at}ucsd.edu.\n\n [1]: #xref-corresp-1-1

The transport and translation of dendritic mRNAs by RNA-binding proteins (RBPs) allows for spatially restricted gene expression in neuronal processes. Although local translation in neuronal dendrites is now well documented, there is little evidence for corresponding effects on local synaptic function. Here, we report that the RBP Sam68 promotes the localization and translation of Arc mRNA preferentially in distal dendrites of rodent hippocampal CA1 pyramidal neurons. Consistent with Arc function in translation-dependent synaptic plasticity, we find that Sam68 knockout (KO) mice display impaired metabotropic glutamate-receptor-dependent long-term depression (mGluR-LTD) and impaired structural plasticity exclusively at distal Schaffer-collateral synapses. Moreover, by using quantitative proteomics, we find that the Sam68 interactome contains numerous regulators of mRNA translation and synaptic function. This work identifies an important player in Arc expression, provides a general framework for Sam68 regulation of protein synthesis, and uncovers a mechanism that enables the precise spatiotemporal expression of long-term plasticity throughout neurons.

Depression leads to significant impairment in daily function. The prolonged time course necessary for current pharmacological treatment may extended suffering and increase risk of suicide. Acute administration of ketamine rapidly alleviates depressive symptoms and reduces suicidality. Ketamine is a non-competitive antagonist of the NMDA receptor but also displays activity on a wide variety of neuronal receptors. Recent studies suggest that the effects of ketamine may be mediated by a variety of systems including AMPA, and opiate receptors.

Which neural circuits undergo synaptic changes when an animal learns? Although it is widely accepted that changes in synaptic strength underlie many forms of learning and memory, it remains challenging to connect changes in synaptic strength at specific neural pathways to specific behaviors and memories. Here we introduce SYNPLA (SYNaptic Proximity Ligation Assay), a synapse-specific, high-throughput and potentially brain-wide method capable of detecting circuit-specific learning-induced synaptic plasticity.

Neuronal activity in the lateral habenula (LHb), a brain region implicated in depression [C. D. Proulx, O. Hikosaka, R. Malinow, Nat. Neurosci. 17,1146-1152 (2014)], decreases during reward and increases during punishment or reward omission [M. Matsumoto, O. Hikosaka, Nature 447,1111-1115 (2007)]. While stress is a major risk factor for depression and strongly impacts the LHb, its effect on LHb reward signals is unknown. Here we image LHb neuronal activity in behaving mice and find that acute stress transforms LHb reward responses into punishment-like neural signals; punishment-like responses to reward omission also increase. These neural changes matched the onset of anhedonic behavior and were specific to LHb neurons that distinguished reward and its omission. Thus, stress distorts LHb responsivity to positive and negative feedback, which could bias individuals toward negative expectations, a key aspect of the proposed pathogenesis of depression [A. T. Beck, Depression: Clinical, Experimental, and Theoretical Aspects, sixth Ed (1967)].

Depression leads to significant impairment in daily function. The prolonged time course necessary for current pharmacological treatment may extend suffering, and increase risk of suicide. Therefore, development of rapid treatments may be helpful by speeding recovery time and reducing suicidality. Two treatments with reproducible clinical efficacy are total sleep deprivation and ketamine administration. Amazingly, these treatments not only alleviate depressive symptoms in refractory patients, but also rapidly reduce suicidality. We used an inbred line of congenital learned helplessness (cLH) rats, a validated model of Major Depressive Disorder (MDD), to examine the synaptic effects of both sleep deprivation and ketamine administration. These rats have a hyperactive lateral habenula (LHb), an epithalamic nucleus that regulates dopamine release from the VTA. Hyperactivity in the habenula leads to decreased dopamine release from the VTA, and depression-like symptoms in these rodents.

Which neural circuits undergo synaptic changes when an animal learns? Although it is widely accepted that changes in synaptic strength underline many forms of learning and memory, it remains challenging to connect changes in synaptic strength at specific neural pathways to specific behaviors and mem ories. Here we introduce SYNPLA (SYNaptic Proxim ity Ligatio n Assay), a synapse-specific, high-throughput an d potentially brain-wid e method capable of detecting circuit-specific learning-induced synaptic piasticity.

N-methyl-d-aspartate receptors (NMDARs) have multiple prominent roles in CNS function but their excessive or insufficient activity contributes to neuropathological/psychiatric disorders. Consequently, a variety of positive and negative allosteric modulators (PAMs and NAMs, respectively) have recently been developed. Although these modulators bind to extracellular domains, in the present report we find that the NMDAR’s intracellular C-terminal domains (CTDs) significantly influence PAM/NAM activity. GluN2 CTD deletion robustly affected NAM and PAM activity with both enhancing and inhibiting effects that were compound-specific and NMDAR subunit-specific. In three cases, individual PAMs became NAMs at specific GluN2-truncated receptors. In contrast to GluN2, GluN1 CTD removal only reduced PAM activity of UBP684 and CIQ, and did not affect NAM activity. Consistent with these findings, agents altering phosphorylation state or intracellular calcium levels displayed receptor-specific and compound-specific effects on PAM activity. It is possible that the GluN2′s M4 domain transmits intracellular modulatory signals from the CTD to the M1/M4 channel gating machinery and that this site is a point of convergence in the direct or indirect actions of several PAMs/NAMs thus rendering them sensitive to CTD status. Thus, allosteric modulators are likely to have a marked and varied sensitivity to post-translational modifications, protein-protein associations, and intracellular ions. The interaction between PAM activity and NMDAR CTDs appears reciprocal. GluN1 CTD-deletion eliminated UBP684, but not pregnenolone sulfate (PS), PAM activity. And, in the absence of agonists, UBP684, but not PS, was able to promote movement of fluorescently-tagged GluN1-CTDs. Thus, it may be possible to pharmacologically target NMDAR metabotropic activity in the absence of channel activation.