Kevin J. Bender

Two Coincidence Detectors for Spike Timing-Dependent Plasticity in Somatosensory Cortex

Many cortical synapses exhibit spike timing-dependent plasticity (STDP) in which the precise timing of presynaptic and postsynaptic spikes induces synaptic strengthening [long-term potentiation (LTP)] or weakening [long-term depression (LTD)]. Standard models posit a single, postsynaptic, NMDA receptor-based coincidence detector for LTP and LTD components of STDP. We show instead that STDP at layer 4 to layer 2/3 synapses in somatosensory (S1) cortex involves separate calcium sources and coincidence detection mechanisms for LTP and LTD. LTP showed classical NMDA receptor dependence. LTD was independent of postsynaptic NMDA receptors and instead required group I metabotropic glutamate receptors and calcium from voltage-sensitive channels and IP3 receptor-gated stores. Downstream of postsynaptic calcium, LTD required retrograde endocannabinoid signaling, leading to presynaptic LTD expression, and also required activation of apparently presynaptic NMDA receptors. These LTP and LTD mechanisms detected firing coincidence on ∼25 and ∼125 ms time scales, respectively, and combined to implement the overall STDP rule. These findings indicate that STDP is not a unitary process and suggest that endocannabinoid-dependent LTD may be relevant to cortical map plasticity.

Axon Initial Segment Ca2+ Channels Influence Action Potential Generation and Timing

Although action potentials are typically generated in the axon initial segment (AIS), the timing and pattern of action potentials are thought to depend on inward current originating in somatodendritic compartments. Using two-photon imaging, we show that T- and R-type voltage-gated Ca(2+) channels are colocalized with Na(+) channels in the AIS of dorsal cochlear nucleus interneurons and that activation of these Ca(2+) channels is essential to the generation and timing of action potential bursts known as complex spikes. During complex spikes, where Na(+)-mediated spikelets fire atop slower depolarizing conductances, selective block of AIS Ca(2+) channels delays spike timing and raises spike threshold. Furthermore, AIS Ca(2+) channel block can decrease the number of spikelets within a complex spike and can even block single, simple spikes. Similar results were found in cortex and cerebellum. Thus, voltage-gated Ca(2+) channels at the site of spike initiation play a key role in generating and shaping spike bursts.

Synaptic basis for whisker deprivation-induced synaptic depression in rat somatosensory cortex.

Whisker deprivation weakens excitatory layer 4 (L4) inputs to L2/3 pyramidal cells in rat primary somatosensory (S1) cortex, which is likely to contribute to whisker map plasticity. This weakening has been proposed to represent long-term depression (LTD) induced by sensory deprivation in vivo. Here, we studied the synaptic expression mechanisms for deprivation-induced weakening of L4-L2/3 inputs and assessed its similarity to LTD, which is known to be expressed presynaptically at L4-L2/3 synapses. Whisker deprivation increased the paired pulse ratio at L4-L2/3 synapses and slowed the use-dependent block of NMDA receptor currents by MK-801 [(5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate], indicating that deprivation reduced transmitter release probability at these synapses. In contrast, deprivation did not alter either miniature EPSC amplitude in L2/3 neurons or the amplitude of quantal L4-L2/3 synaptic responses measured in strontium, indicating that postsynaptic responsiveness was unchanged. In young postnatal day 12 (P12) rats, at least 4 d of deprivation were required to significantly weaken L4-L2/3 synapses. Similar weakening occurred when deprivation began at older ages (P20), when synapses are mostly mature, indicating that weakening is unlikely to represent a failure of synaptic maturation but instead represents a reduction in the strength of existing synapses. Thus, whisker deprivation weakens L4-L2/3 synapses by decreasing presynaptic function, similar to known LTD mechanisms at this synapse.

The Physiology of the Axon Initial Segment

The action potential generally begins in the axon initial segment (AIS), a principle confirmed by 60 years of research; however, the most recent advances have shown that a very rich biology underlies this simple observation. The AIS has a remarkably complex molecular composition, with a wide variety of ion channels and attendant mechanisms for channel localization, and may feature membrane domains each with distinct roles in excitation. Its function may be regulated in the short term through the action of neurotransmitters, in the long term through activity- and Ca(2+)-dependent processes. Thus, the AIS is not merely the beginning of the axon, but rather a key site in the control of neuronal excitability.

Short- and Long-Term Plasticity at the Axon Initial Segment

The axon initial segment (AIS) is a highly specialized neuronal subregion that is the site of action potential initiation and the boundary between axonal and somatodendritic compartments. In recent years, our understanding of the molecular structure of the AIS, its maturation, and its multiple fundamental roles in neuronal function has seen major advances. We are beginning to appreciate that the AIS is dynamically regulated, both over short timescales via adaptations in ion channel function, and long timescales via activity-dependent structural reorganization. Here, we review results from this emerging field highlighting how structural and functional plasticity relate to the development of the initial segment, and to neuronal disorders linked to AIS dysfunction.

Medial Amygdalar Aromatase Neurons Regulate Aggression in Both Sexes

Aromatase-expressing neuroendocrine neurons in the vertebrate male brain synthesize estradiol from circulating testosterone. This locally produced estradiol controls neural circuits underlying courtship vocalization, mating, aggression, and territory marking in male mice. How aromatase-expressing neuronal populations control these diverse estrogen-dependent male behaviors is poorly understood, and the function, if any, of aromatase-expressing neurons in females is unclear. Using targeted genetic approaches, we show that aromatase-expressing neurons within the male posterodorsal medial amygdala (MeApd) regulate components of aggression, but not other estrogen-dependent male-typical behaviors. Remarkably, aromatase-expressing MeApd neurons in females are specifically required for components of maternal aggression, which we show is distinct from intermale aggression in pattern and execution. Thus, aromatase-expressing MeApd neurons control distinct forms of aggression in the two sexes. Moreover, our findings indicate that complex social behaviors are separable in a modular manner at the level of genetically identified neuronal populations.

Dopaminergic Modulation of Axon Initial Segment Calcium Channels Regulates Action Potential Initiation

Action potentials initiate in the axon initial segment (AIS), a specialized compartment enriched with Na(+) and K(+) channels. Recently, we found that T- and R-type Ca(2+) channels are concentrated in the AIS, where they contribute to local subthreshold membrane depolarization and thereby influence action potential initiation. While periods of high-frequency activity can alter availability of AIS voltage-gated channels, mechanisms for long-term modulation of AIS channel function remain unknown. Here, we examined the regulatory pathways that control AIS Ca(2+) channel activity in brainstem interneurons. T-type Ca(2+) channels were downregulated by dopamine receptor activation acting via protein kinase C, which in turn reduced neuronal output. These effects occurred without altering AIS Na(+) or somatodendritic T-type channel activity and could be mediated by endogenous dopamine sources present in the auditory brainstem. This pathway represents a new mechanism to inhibit neurons by specifically regulating Ca(2+) channels directly involved in action potential initiation.

Endocannabinoid signaling is required for development and critical period plasticity of the whisker map in somatosensory cortex.

Type 1 cannabinoid (CB1) receptors mediate widespread synaptic plasticity, but how this contributes to systems-level plasticity and development in vivo is unclear. We tested whether CB1 signaling is required for development and plasticity of the whisker map in rat somatosensory cortex. Treatment with the CB1 antagonist AM251 during an early critical period for layer (L) 2/3 development (beginning postnatal day [P] 12-16) disrupted whisker map development, leading to inappropriate whisker tuning in L2/3 column edges and a blurred map. Early AM251 treatment also prevented experience-dependent plasticity in L2/3, including deprivation-induced synapse weakening and weakening of deprived whisker responses. CB1 blockade after P25 did not disrupt map development or plasticity. AM251 had no acute effect on sensory-evoked spiking and only modestly affected field potentials, suggesting that plasticity effects were not secondary to gross activity changes. These findings implicate CB1-dependent plasticity in systems-level development and early postnatal plasticity of the whisker map.

Control of firing patterns through modulation of axon initial segment T-type calcium channels

Non‐technical summary  Spontaneous bursting, in which neurons spontaneously fire clusters of action potentials, underlies a variety of neuronal functions, including breathing and sleep rhythms. The cellular mechanisms that underlie spontaneous burst generation are poorly understood. Here, we show that calcium‐permeable ion channels, recently shown to be localized to the site of action potential initiation in the initial segment of axons, are crucial for the generation of spontaneous bursts in auditory brainstem neurons. Block of calcium influx at this site was sufficient to convert spontaneous bursting neurons into neurons which fired in a regular pattern. Block could also be mediated by the neurotransmitter dopamine, which alters calcium channel activity through a kinase dependent mechanism. These results are the first to show that spontaneous firing mode can be controlled by neuromodulators acting on a specific cellular compartment, and highlight the importance of these calcium channels in the generation of spontaneous neuronal rhythm.

Postnatal development of cannabinoid receptor type 1 expression in rodent somatosensory cortex.

Endocannabinoids are powerful modulators of synaptic transmission that act on presynaptic cannabinoid receptors. Cannabinoid receptor type 1 (CB1) is the dominant receptor in the CNS, and is present in many brain regions, including sensory cortex. To investigate the potential role of CB1 receptors in cortical development, we examined the developmental expression of CB1 in rodent primary somatosensory (barrel) cortex, using immunohistochemistry with a CB1-specific antibody. We found that before postnatal day (P) 6, CB1 receptor staining was present exclusively in the cortical white matter, and that CB1 staining appeared in the gray matter between P6 and P20 in a specific laminar pattern. CB1 staining was confined to axons, and was most prominent in cortical layers 2/3, 5a, and 6. CB1 null (-/-) mice showed altered anatomical barrel maps in layer 4, with enlarged inter-barrel septa, but normal barrel size. These results indicate that CB1 receptors are present in early postnatal development and influence development of sensory maps.