The single dendritic branch as a fundamental functional unit in the nervous system

Functional connectivity between the hippocampus and prefrontal cortex (PFC) is essential for associative recognition memory and working memory. Disruption of hippocampal-PFC synchrony occurs in schizophrenia, which is characterized by hypofunction of NMDA receptor (NMDAR)-mediated transmission. We demonstrate that activity of dopamine D2-like receptors (D2Rs) leads selectively to long-term depression (LTD) of hippocampal-PFC NMDAR-mediated synaptic transmission. We show that dopamine-dependent LTD of NMDAR-mediated transmission profoundly disrupts normal synaptic transmission between hippocampus and PFC. These results show how dopaminergic activation induces long-term hypofunction of NMDARs, which can contribute to disordered functional connectivity, a characteristic that is a hallmark of psychiatric disorders such as schizophrenia.T he hippocampus to medial prefrontal cortex (PFC) projection is important for executive function and working and long-term memory (1, 2). Glutamatergic neurons of the ventral hippocampal cornu ammonis 1 (CA1) region project directly to layers 2-6 of ipsilateral PFC, and this connection synchronizes PFC and hippocampal activity during particular behavioral conditions (3-5). Disruption of hippocampal-PFC synchrony is associated with cognitive deficits that occur in disorders such as schizophrenia (6). Hippocampal-PFC uncoupling can be achieved by NMDA receptor (NMDAR) antagonism (7), and NMDAR hypofunction is a recognized feature of schizophrenia (8). However, it is unclear, first, how changes in NMDAR function at this synapse may arise, and second, how NMDAR hypofunction affects hippocampal-PFC synaptic transmission.Canonically, NMDARs are considered to contribute little to single synaptic events, but the slow kinetics of NMDARs contribute to maintaining depolarization, leading to the generation of bursts of action potentials (9-13). Furthermore, NMDARs coordinate spike timing relative to the phase of field potential oscillations (14, 15). NMDAR transmission itself undergoes synaptic plasticity (16,17), and this can have a profound effect on sustained depolarization, burst firing, synaptic integration, and metaplasticity (9,11,18,19). In PFC, NMDARs are oppositely regulated by dopamine receptors; D1-like receptors (D1Rs) potentiate and D2-like receptors (D2Rs) depress NMDAR currents (20). Interestingly, NMDAR hypofunction (8, 21) and dopamine D2 receptor activity (22) are potentially converging mechanisms contributing to schizophrenia (23).We now examine the contribution of NMDARs to transmission at the hippocampal-PFC synapse. We show that NMDAR activity provides sustained depolarization that can trigger action potentials during bursts of hippocampal input to PFC. We next demonstrate that dopamine D2 receptor-dependent long-term depression (LTD) of NMDAR transmission profoundly attenuates summation of synaptic transmission and neuronal firing at the hippocampal-PFC input. These findings allow for a mechanistic understanding of how alterations in dopamine and NMDAR function can lead t...

Section: Discussionmentioning

confidence: 64%

“…Canonically, NMDARs are considered to contribute little to single synaptic events, but the slow kinetics of NMDARs contribute to maintaining depolarization, leading to the generation of bursts of action potentials (9)(10)(11)(12)(13). Furthermore, NMDARs coordinate spike timing relative to the phase of field potential oscillations (14,15).…”

mentioning

confidence: 99%

Disruption of hippocampal–prefrontal cortex activity by dopamine D2R-dependent LTD of NMDAR transmission

Banks

Burroughs

Barker

et al. 2015

“…Furthermore, an interesting consequence of minimizing wiring to target synapses is that synapses that are close together are more likely to be linked by the same stretch of dendrite and therefore involved in a local computation (31)(32)(33), such that geometry is a key determinant of information processing. There is increasing evidence that such sophisticated local processing may be carried out within the dendritic tree (34,35), with nonlinear interactions between synaptic inputs shaping the output of the neuron (36)(37)(38)(39). We therefore predict it will be fruitful to study how the scaling laws of wiring and branching place constraints on the overall computational power of single neurons.…”

Section: Discussionmentioning

confidence: 99%

A scaling law derived from optimal dendritic wiring

Cuntz

Mathy

Häusser

2012

Self Cite

111

The wide diversity of dendritic trees is one of the most striking features of neural circuits. Here we develop a general quantitative theory relating the total length of dendritic wiring to the number of branch points and synapses. We show that optimal wiring predicts a 2/3 power law between these measures. We demonstrate that the theory is consistent with data from a wide variety of neurons across many different species and helps define the computational compartments in dendritic trees. Our results imply fundamentally distinct design principles for dendritic arbors compared with vascular, bronchial, and botanical trees.computational neuroscience | branching | dendrite | morphology | minimum spanning tree O ne of the main roles of dendrites is to connect a neuron to its synaptic inputs. To interpret neural connectivity from morphological data, it is important to understand the relationship between dendrite shape and synaptic input distribution (1-4). As early as the end of the 19th century (5), it was suggested that dendrites optimize connectivity in terms of cable length and conduction time costs, and a number of recent studies have supported the idea that optimal wiring explains dendritic branching patterns using simulations (6-8) or by reasoning from first principles (1, 2, 9, 10). However, although dendrite length is the most common measure for molecular studies of dendritic growth (11), its relationship to dendritic branching and the number of synaptic contacts has not been elucidated. Understanding this relationship should provide crucial constraints for circuit structure and function. Here we directly test the hypothesis that neurons wire up a space in an optimal way by studying the consequences for dendrite length and branching complexity. We derive a simple equation that directly relates dendrite length with the number of branch points, dendrite spanning volume, and number of synapses. ResultsRelating Total Dendritic Length to Optimal Wiring. We assume that a dendritic tree of total length L connects n target points distributed over a volume V (Fig. 1A). Each target point occupies an average volume V =n. A tree that optimizes wiring will tend to connect points to their nearest neighbors, which are on average located at distances proportional to ðV =nÞ 1=3 . We need at least n such dendritic sections to make up the tree. The total length L of these sections sums up toThis result shows that a 2/3 power law relationship between L and n (12) provides a lower bound for the total dendritic length, where c is a proportionality constant. Approximating the volume around each target point by a sphere, then c ¼ ð3=4πÞ 1=3 , and each dendritic section corresponds to the radius of a sphere, giving(SI Text and Fig. S1). Importantly, assuming a constant ratio between the number of branch points, bp and the number of target points (which is addressed later), this assumption also results in a 2/3 power law between wiring length and the number of branch points. Supporting these intuitive derivations of power laws, there ...

“…Much interest has been placed on the role of individual dendritic branches in determining neuronal output (1). The single branch has been hypothesized to function as a unit of plasticity (2), protein synthesis (3), and synaptic integration (4).…”

mentioning

confidence: 99%

Multibranch activity in basal and tuft dendrites during firing of layer 5 cortical neurons in vivo

Hill

Varga

Jia

et al. 2013

Layer 5 pyramidal neurons process information from multiple cortical layers to provide a major output of cortex. Because of technical limitations it has remained unclear how these cells integrate widespread synaptic inputs located in distantly separated basal and tuft dendrites. Here, we obtained in vivo twophoton calcium imaging recordings from the entire dendritic field of layer 5 motor cortex neurons. We demonstrate that during subthreshold activity, basal and tuft dendrites exhibit spatially localized, small-amplitude calcium transients reflecting afferent synaptic inputs. During action potential firing, calcium signals in basal dendrites are linearly related to spike activity, whereas calcium signals in the tuft occur unreliably. However, in both dendritic compartments, spike-associated calcium signals were uniformly distributed throughout all branches. Thus, our data support a model of widespread, multibranch integration with a direct impact by basal dendrites and only a partial contribution on output signaling by the tuft.excitatory synapses | dendritic integration | mouse motor cortex P yramidal neurons feature extensive dendritic arborizations that receive and process widespread synaptic input. Much interest has been placed on the role of individual dendritic branches in determining neuronal output (1). The single branch has been hypothesized to function as a unit of plasticity (2), protein synthesis (3), and synaptic integration (4). Moreover, single dendritic branches have been shown to generate spatially restricted regenerative events, the so-called dendritic spikes, which can process and amplify local input (5). These features raise the question of whether the input-output relation of a cortical neuron is influenced primarily by single dendrites or by multibranch activity.Layer 5 (L5) pyramidal neurons serve as the major output cell type of neocortex. Their morphology is characterized by a set of basal dendrites as well as a set of distal tuft dendrites that extend into layer 1 and are separated from the soma by a long apical trunk (6). These compartments are known to be specialized in terms of the type of synaptic input that they receive (7). Furthermore, in vitro studies of dendritic physiology have revealed several active dendritic signals in these compartments such as back-propagation of action potentials (bAPs) (8, 9), NMDA spikes resulting from clustered synaptic activation (5), and calcium spikes initiated in the apical trunk (10, 11). Despite the presence of these dendritic specializations, little is known about the importance of these features for in vivo function. Previous in vivo studies were limited by the technical challenges of recording from deep basal structures in L5 (12) or of recording multiple individual dendrites simultaneously from the same neuron (13). A complete understanding of dendritic integration in L5 pyramidal neurons requires in vivo data from both the basal and tuft compartments with single dendritic branch resolution.Here we address the question of multibranch activi...