The magnitude and direction of synaptic plasticity can be determined by the precise timing of presynaptic and postsynaptic action potentials on a millisecond timescale. In vivo, however, neural activity has structure on longer timescales. Here we show that plasticity at the CA3-CA1 synapse depends strongly on parameters other than millisecond spike timing. As a result, the notion that a single spiketiming-dependent plasticity (STDP) rule alone can fully describe the mapping between neural activity and synapse strength is invalid. We have begun to explore the influence of additional behaviorally relevant activity parameters on STDP and found conditions under which underlying spike-timing-dependent rules for potentiation and depression can be separated from one another. Potentiation requires postsynaptic burst firing at 5 Hz or higher, a firing pattern that occurs during the theta rhythm. Potentiation is measurable after only tens of presynaptic-before-postsynaptic pairings. Depression requires hundreds of pairings but has less stringent long timescale requirements and broad timing dependence. By varying these parameters, we obtain STDP curves that are long-term potentiation only, bidirectional, or long-term depression only. This expanded description of the CA3-CA1 learning rule reconciles apparent contradictions between spike-timing-dependent plasticity and previous work at CA3-CA1 synapses.

Biological information storage events are often rapid transitions between discrete states. In neural systems, the initiation of bidirectional plasticity by all-or-none events may help confer robustness on memory storage. Here, we report that at CA3-CA1 hippocampal synapses, individual potentiation and depression plasticity events are discrete and heterogeneous in nature. Individual synapses began from extreme high and low strength states. Unitary plasticity events were all-or-none and drove synaptic strength between extremes in <1 min. Under naïve conditions, approximately three-fourths of synapses began in a low-strength state. The timing of these unitary events can account for the time course of macroscopic synaptic plasticity.B oth increases (long-term potentiation, LTP) (1) and decreases (long-term depression, LTD) in synaptic strength are almost always measured macroscopically across populations of synaptic contacts (2). Macroscopic recordings, in which plasticity appears as a graded phenomenon, have ranged from extracellular recordings from many thousands of synapses (3, 4) to single-cell recordings (5), including recordings from connected pairs of nearby single neurons representing summed activity from order 10 synaptic terminals (6, 7).Plasticity has been described in terms of transitions among distinct states (7). However, the concept of synaptic states has not been explored in terms of unitary synaptic strength. Characterizing plasticity at this level requires observations from putative single terminals.An attractive system for studying unitary plasticity events is the hippocampal CA3-CA1 pathway (4, 8), where connected CA3 and CA1 neurons communicate typically by a single synaptic contact (9). Minimal stimulation techniques (10-12) allow plasticity transitions to be localized in time as they occur (13). Previous work (13) indicates that unitary synaptic potentiation, at least in its initial stages, may be an all-or-none event.Here, we report on the unitary properties of the initiation of potentiation and depression at CA3-CA1 synapses. We find that both potentiation and depression events are all-or-none and sudden. These events can be reconstituted to account for the time course of plasticity on a macroscopic scale. MethodsSlice Preparation. Transverse hippocampal slices (300 m) from Sprague-Dawley rats (postnatal day 13-21) were cut in ice-cold artificial cerebrospinal fluid (ACSF) comprising (in mM) 126 NaCl, 3 KCl, 1 NaH 2 PO 4 , 25 D-glucose, 25 NaHCO 3 , 2 CaCl 2 , and 1 MgCl 2 saturated with 95% O 2 ͞5% CO 2 , incubated at 34°C for 10-15 min, and transferred to a room-temperature interface chamber for Ն60 min before recording. The cutting angle was such that excitatory postsynaptic current (EPSC) size in response to stimulation of stratum radiatum decreased rapidly as the stimulation electrode was moved toward CA3. By using this cutting angle and moving the stimulation electrode as far toward CA3 as possible, we reduced the likelihood of stimulating multiple connected axons. For recordings, slic...

Spike timing dependent plasticity (STDP) is a phenomenon in which the precise timing of spikes affects the sign and magnitude of changes in synaptic strength. STDP is often interpreted as the comprehensive learning rule for a synapse – the “first law” of synaptic plasticity. This interpretation is made explicit in theoretical models in which the total plasticity produced by complex spike patterns results from a superposition of the effects of all spike pairs. Although such models are appealing for their simplicity, they can fail dramatically. For example, the measured single-spike learning rule between hippocampal CA3 and CA1 pyramidal neurons does not predict the existence of long-term potentiation one of the best-known forms of synaptic plasticity. Layers of complexity have been added to the basic STDP model to repair predictive failures, but they have been outstripped by experimental data. We propose an alternate first law: neural activity triggers changes in key biochemical intermediates, which act as a more direct trigger of plasticity mechanisms. One particularly successful model uses intracellular calcium as the intermediate and can account for many observed properties of bidirectional plasticity. In this formulation, STDP is not itself the basis for explaining other forms of plasticity, but is instead a consequence of changes in the biochemical intermediate, calcium. Eventually a mechanism-based framework for learning rules should include other messengers, discrete change at individual synapses, spread of plasticity among neighboring synapses, and priming of hidden processes that change a synapse's susceptibility to future change. Mechanism-based models provide a rich framework for the computational representation of synaptic plasticity.

Overexpression and enhanced activity of insulin-like growth factor

Background Examining transcriptional regulation by antidepressants in key neural circuits implicated in depression, and understanding the relationship to transcriptional mechanisms of susceptibility and natural resilience, may help in the search for new therapeutics. Given the heterogeneity of treatment response in human populations, examining both treatment response and non-response is critical. Methods We compared the effects of a conventional monoamine-based tricyclic antidepressant, imipramine, and a rapidly acting, non-monoamine-based antidepressant, ketamine, in mice subjected to chronic social defeat stress, a validated depression model, and used RNA-sequencing to analyze transcriptional profiles associated with susceptibility, resilience and antidepressant response and non-response in prefrontal cortex (PFC), nucleus accumbens, hippocampus, and amygdala. Results We identified similar numbers of responders and non-responders following ketamine or imipramine treatment. Ketamine induced more expression changes in hippocampus; imipramine induced more expression changes in nucleus accumbens and amygdala. Transcriptional profiles in treatment responders were most similar in PFC. Non-response reflected both the lack of response-associated gene expression changes and unique gene regulation. In responders, both drugs reversed susceptibility-associated transcriptional changes as well as induced resilience-associated transcription in PFC. Conclusions We generated a uniquely large resource of gene expression data in four inter-connected limbic brain regions implicated in depression and its treatment with imipramine or ketamine. Our analyses highlight the PFC as a key site of common transcriptional regulation by both antidepressant drugs and in both reversing susceptibility- and inducing resilience-associated molecular adaptations. In addition, we found region-specific effects of each drug suggesting both common and unique effects of imipramine versus ketamine.