Changes In Excitatory Input Research Articles

Tauopathy and alcohol consumption interact to alter locus coeruleus excitatory transmission and excitability in male and female mice.

Alcohol use disorder is a major public health concern in the United States. Recent work has suggested a link between chronic alcohol consumption and the development of tauopathy disorders, such as Alzheimer's disease and frontotemporal dementia. However, relatively little work has investigated changes in neural circuitry involved in both tauopathy disorders and alcohol use disorder. The locus coeruleus (LC) is the major noradrenergic nucleus in the brain and is one of the earliest sites to be affected by tau lesions. The LC is also implicated in the rewarding effects of ethanol and alcohol withdrawal. In this study we assessed effects of long-term ethanol consumption and tauopathy on the physiology of LC neurons. Male and female P301S mice, a humanized transgenic mouse model of tauopathy, underwent 16 weeks of intermittent access to 20% ethanol from 3 to 7 months of age. We observed higher total alcohol consumption in female mice regardless of genotype. Male P301S mice consumed more ethanol and had a greater preference for ethanol than wild-type (WT) males. At the end of the drinking study, LC function was assessed using exvivo whole cell electrophysiology. We found significant changes in excitatory inputs to the LC due to both ethanol and genotype. We found significantly increased excitability of the LC due to ethanol with greater effects in female P301S mice than in female WT mice. Our study identifies significant changes in the LC due to interactions between tauopathy and long-term ethanol use. These findings could have important implications regarding LC activity and changes in behavior due to both ethanol- and tauopathy-related dementia.

Sodium channels implement a molecular leaky integrator that detects action potentials and regulates neuronal firing.

Voltage-gated sodium channels play a critical role in cellular excitability, amplifying small membrane depolarizations into action potentials. Interactions with auxiliary subunits and other factors modify the intrinsic kinetic mechanism to result in new molecular and cellular functionality. We show here that sodium channels can implement a molecular leaky integrator, where the input signal is the membrane potential and the output is the occupancy of a long-term inactivated state. Through this mechanism, sodium channels effectively measure the frequency of action potentials and convert it into Na+ current availability. In turn, the Na+ current can control neuronal firing frequency in a negative feedback loop. Consequently, neurons become less sensitive to changes in excitatory input and maintain a lower firing rate. We present these ideas in the context of rat serotonergic raphe neurons, which fire spontaneously at low frequency and provide critical neuromodulation to many autonomous and cognitive brain functions.

Changes in motor unit discharge patterns following strength training.

Changes in motor unit discharge patterns following strength training.

Regulation of rhythm genesis by volume-limited, astroglia-like signals in neural networks.

Rhythmic activity of the brain often depends on synchronized spiking of interneuronal networks interacting with principal neurons. The quest for physiological mechanisms regulating network synchronization has therefore been firmly focused on synaptic circuits. However, it has recently emerged that synaptic efficacy could be influenced by astrocytes that release signalling molecules into their macroscopic vicinity. To understand how this volume-limited synaptic regulation can affect oscillations in neural populations, here we explore an established artificial neural network mimicking hippocampal basket cells receiving inputs from pyramidal cells. We find that network oscillation frequencies and average cell firing rates are resilient to changes in excitatory input even when such changes occur in a significant proportion of participating interneurons, be they randomly distributed or clustered in space. The astroglia-like, volume-limited regulation of excitatory synaptic input appears to better preserve network synchronization (compared with a similar action evenly spread across the network) while leading to a structural segmentation of the network into cell subgroups with distinct firing patterns. These observations provide us with some previously unknown insights into the basic principles of neural network control by astroglia.

Reduced inhibitory gate in the barrel cortex of Neuroligin3R451C knock-in mice, an animal model of autism spectrum disorders.

Neuroligins are postsynaptic adhesion molecules that interacting with presynaptic neurexins ensure the cross‐talk between pre‐ and postsynaptic specializations. Rare mutations in neurexin–neuroligin genes have been linked to autism spectrum disorders (ASDs). One of these, the R451C mutation of the gene encoding for Neuroligin3 (Nlgn3), has been found in patients with familial forms of ASDs. Animals carrying this mutation (NL3R451C knock‐in mice) exhibit impaired social behaviors, reminiscent of those observed in ASD patients, associated with major alterations in both GABAergic and glutamatergic transmission, which vary among different brain regions and at different developmental stages. Here, pair recordings from parvalbumin‐ (PV) expressing basket cells and spiny neurons were used to study GABAergic synaptic signaling in layer IV barrel cortex of NL3R451C mutant mice. We found that the R451C mutation severely affects the probability of GABA release from PV‐expressing basket cells, responsible for controlling via thalamo‐cortical inputs the feed‐forward inhibition. No changes in excitatory inputs to parvalbumin‐positive basket cells or spiny neurons were detected. These data clearly show that primary targets of the NL3 mutation are PV‐expressing basket cells, independently of the brain region where they are localized. Changes in the inhibitory gate of layer IV somatosensory cortex may alter sensory processing in ASD patients leading to misleading sensory representations with difficulties to combine pieces of information into a unified perceptual whole.

Impaired hippocampal rhythmogenesis in a mouse model of mesial temporal lobe epilepsy

Mesial temporal lobe epilepsy (mTLE) is one of the most common forms of epilepsy, characterized by hippocampal sclerosis and memory deficits. Injection of kainic acid (KA) into the dorsal hippocampus of mice reproduces major electrophysiological and histopathological characteristics of mTLE. In extracellular recordings from the morphologically intact ventral hippocampus of KA-injected epileptic mice, we found that theta-frequency oscillations were abolished, whereas gamma oscillations persisted both in vivo and in vitro. Whole-cell recordings further showed that oriens-lacunosum-moleculare (O-LM) interneurons, key players in the generation of theta rhythm, displayed marked changes in their intrinsic and synaptic properties. Hyperpolarization-activated mixed cation currents (Ih) were significantly reduced, resulting in an increase in the input resistance and a hyperpolarizing shift in the resting membrane potential. Additionally, the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) was increased, indicating a stronger excitatory input to these neurons. As a consequence, O-LM interneurons increased their firing rate from theta to gamma frequencies during induced network activity in acute slices from KA-injected mice. Thus, our physiological data together with network simulations suggest that changes in excitatory input and synaptic integration in O-LM interneurons lead to impaired rhythmogenesis in the hippocampus that in turn may underlie memory deficit.

Chapter 29 Anatomical origins of the classical receptive field and modulatory surround field of single neurons in macaque visual cortical area V1

From the analyses of our own and others' anatomical and physiological data for the macaque visual system, we arrive at a conclusion that three pathways can provide the V1 neuron with access to information from the visual field and affect its response. First, direct thalamic input can determine the size of the initial activating RF at high contrast. Second, lateral connections can enlarge the RF at low contrast by pooling information from larger regions of cortex that are otherwise ineffective when high contrast thalamic input is driving the cortical neuron. Thirdly, feedback from extrastriate cortex (possibly together with overlap or interdigitation of coactive lateral connectional fields within V1) can provide a large and stimulus specific surround modulatory field. The stimulus specificity of the interactions between the center and surround fields, may be due to the orderly, matching structure and different scales of intra-areal and feedback projection excitatory pathways. The observed activity changes of single recorded excitatory neurons could be a result of the relative weight of excitation on the excitatory neurons themselves and on local inhibitory interneurons that synapse on them. Inhibitory basket neurons, driven by the local excitatory neurons, could govern local interactions between cortical patches of different tuning properties, resulting in more distant changes in excitatory input in the laterally connected intra-areal neuronal pools.

Long-term enhancement of excitatory synaptic inputs to layer V parahippocampal neurons by low frequency stimulation in rat brain slices

Excitatory inputs to layer V neurons of the parasubiculum and medial entorhinal cortex were examined in rat brain slices with intracellular and field potential recordings. Single extracellular stimuli to layer V evoked subthreshold excitatory postsynaptic potentials (EPSPs) or a long duration (>100 ms) depolarization that sustained high frequency firing. Repetitive stimulation at low frequencies (from 1/10 s to 1/min) induced stable long-lasting decreases in the threshold for firing in individual cells or population events, and also induced stable long-lasting increases in evoked intracellular or field response amplitudes. More stimuli were required to produce the equivalent changes in threshold and amplitude in the presence of MCPG (200 microM). Smaller changes in amplitude, but equivalent changes in threshold were elicited in the presence of CPP (10 microM), or CPPG (20 microM). No changes in threshold or amplitude were detected in the presence of CNQX (10 microM), even when used in combination with picrotoxin (100 microM). EPSP facilitation was enhanced greatly by firing in postsynaptic cells. It is suggested that stable changes in excitatory inputs to layer V parahippocampal neurons involve the activation of NMDA and metabotropic glutamate receptors, but requires AMPA receptor activation and postsynaptic cell firing.

Estrogen Regulates Functional Inhibition of Hippocampal CA1 Pyramidal Cells in the Adult Female Rat

Previous studies have focused considerable attention on the effects of estrogen on excitatory synaptic input to hippocampal CA1 pyramidal cells. Estrogen increases the density of dendritic spines and synapses on CA1 pyramidal cells and increases the sensitivity of these cells to excitatory synaptic input. Little is known, however, about the effects of estrogen on inhibitory synaptic input to CA1 pyramidal cells. We have used immunohistochemistry for glutamic acid decarboxylase and whole-cell voltage-clamp recording of IPSCs and EPSCs at multiple time points after estrogen treatment to (1) investigate estrogen regulation of synaptic inhibition in CA1 and (2) evaluate how estrogen affects the interaction between inhibitory and excitatory input to CA1 pyramidal cells. We find that estrogen transiently suppresses GABA(A)-mediated inhibition of CA1 pyramidal cells at a time point before changes in excitatory input to these cells occur. This finding is consistent with the suggestion that transient disinhibition of CA1 pyramidal cells is involved in estrogen-induced dendritic spine formation. We have also found that at a later time after estrogen, inhibition of CA1 pyramidal cells recovers in parallel with enhancement of NMDA-mediated excitatory input. The concurrent enhancement of GABA(A) and NMDA-mediated input to CA1 pyramidal cells restores a balance of excitatory and inhibitory input to these cells and increases the potential dynamic range of CA1 pyramidal cell responses to synaptic input.

GABAergic Inhibition Antagonizes Adaptive Adjustment of the Owl's Auditory Space Map during the Initial Phase of Plasticity

We studied the influence of GABA-mediated inhibition on adaptive adjustment of the owl's auditory space map during the initial phase of plasticity. Plasticity of the auditory space map was induced by subjecting owls to a chronic prismatic displacement of the visual field. In the initial stages of plasticity, inhibition suppressed responses to behaviorally appropriate, newly functional excitatory inputs. As a result, adaptive changes in excitatory input were only partially expressed as postsynaptic spike activity. This masking effect of inhibition on map plasticity did not depend on the activity of NMDA receptors at the synapses that supported the newly learned responses. On the basis of these results, we propose that the pattern of feedforward inhibition is less dynamic than the pattern of feedforward excitation at the site of plasticity. As a result, initially in the adjustment process the preexisting pattern of feedforward GABAergic inhibition opposes changes in the auditory space map and tends to preserve the established response properties of the network. The implications of this novel role of inhibition for the functional plasticity of the brain are discussed.

Modulation of striatal neuronal activity by glutamate and GABA: iontophoresis in awake, unrestrained rats

To examine the effects of glutamate (GLU) and γ-aminobutyric acid (GABA) and their interactions in the striatum under behaviorally relevant conditions, single-unit recording was combined with microiontophoresis in awake, unrestrained rats. Iontophoretically applied GLU (0–40 nA, 20 s) excited all spontaneously active neurons in dorsal (caudate–putamen) and ventral (accumbens, core) striatum; phasic GLU-induced excitations (mean threshold 19.7 nA) were dose-dependent, inversely correlated with rate of basal activity (excitation limit ∼65 imp/s), and highly stable during repeated GLU applications. GLU also excited silent and sporadically active units, which greatly outnumbered spontaneously active cells, and enhanced neuronal excitations associated with movement. Both spontaneously active and GLU-stimulated striatal neurons were highly sensitive to GABA (0–40 nA, 20 s); most showed short-latency inhibitions during GABA diffusion from the pipette (0 nA) and the response quickly progressed to complete silence with a small increase in current. The GABA-induced inhibition was current-dependent, equally strong on spontaneously active and GLU-stimulated units, and independent of neuronal discharge rate, but less stable than the GLU-induced excitation during repeated drug applications. Prolonged GABA application (0–20 nA, 2–4 min) reduced basal impulse activity, but was less effective in attenuating the neuronal excitations induced by GLU or associated with movement. Our data support the role of GLU afferents in the phasic activation of striatal neurons and suggest that the effects of GLU strongly depend on the level of ongoing neuronal activity. The ability of GABA to modulate both basal and GLU-evoked activity suggests that GABA, released from efferent collaterals and interneurons, plays a critical role in regulating neuronal activity and responsiveness to phasic changes in excitatory input.