Electrical and Network Neuronal Properties Are Preferentially Disrupted in Dorsal, But Not Ventral, Medial Entorhinal Cortex in a Mouse Model of Tauopathy.

The entorhinal cortex (EC) is one of the first areas to be disrupted in neurodegenerative diseases such as Alzheimer's disease and frontotemporal dementia. The responsiveness of individual neurons to electrical and environmental stimuli varies along the dorsal-ventral axis of the medial EC (mEC) in a manner that suggests this topographical organization plays a key role in neural encoding of geometric space. We examined the cellular properties of layer II mEC stellate neurons (mEC-SCs) in rTg4510 mice, a rodent model of neurodegeneration. Dorsoventral gradients in certain intrinsic membrane properties, such as membrane capacitance and afterhyperpolarizations, were flattened in rTg4510 mEC-SCs, while other cellular gradients [e.g., input resistance (Ri), action potential properties] remained intact. Specifically, the intrinsic properties of rTg4510 mEC-SCs in dorsal aspects of the mEC were preferentially affected, such that action potential firing patterns in dorsal mEC-SCs were altered, while those in ventral mEC-SCs were unaffected. We also found that neuronal oscillations in the gamma frequency band (30-80 Hz) were preferentially disrupted in the dorsal mEC of rTg4510 slices, while those in ventral regions were comparatively preserved. These alterations corresponded to a flattened dorsoventral gradient in theta-gamma cross-frequency coupling of local field potentials recorded from the mEC of freely moving rTg4510 mice. These differences were not paralleled by changes to the dorsoventral gradient in parvalbumin staining or neurodegeneration. We propose that the selective disruption to dorsal mECs, and the resultant flattening of certain dorsoventral gradients, may contribute to disturbances in spatial information processing observed in this model of dementia. SIGNIFICANCE STATEMENT: The medial entorhinal cortex (mEC) plays a key role in spatial memory and is one of the first areas to express the pathological features of dementia. Neurons of the mEC are anatomically arranged to express functional dorsoventral gradients in a variety of neuronal properties, including grid cell firing field spacing, which is thought to encode geometric scale. We have investigated the effects of tau pathology on functional dorsoventral gradients in the mEC. Using electrophysiological approaches, we have shown that, in a transgenic mouse model of dementia, the functional properties of the dorsal mEC are preferentially disrupted, resulting in a flattening of some dorsoventral gradients. Our data suggest that neural signals arising in the mEC will have a reduced spatial content in dementia.

Altered Intrinsic Pyramidal Neuron Properties and Pathway-Specific Synaptic Dysfunction Underlie Aberrant Hippocampal Network Function in a Mouse Model of Tauopathy.

The formation and deposition of tau protein aggregates is proposed to contribute to cognitive impairments in dementia by disrupting neuronal function in brain regions, including the hippocampus. We used a battery of in vivo and in vitro electrophysiological recordings in the rTg4510 transgenic mouse model, which overexpresses a mutant form of human tau protein, to investigate the effects of tau pathology on hippocampal neuronal function in area CA1 of 7- to 8-month-old mice, an age point at which rTg4510 animals exhibit advanced tau pathology and progressive neurodegeneration. In vitro recordings revealed shifted theta-frequency resonance properties of CA1 pyramidal neurons, deficits in synaptic transmission at Schaffer collateral synapses, and blunted plasticity and imbalanced inhibition at temporoammonic synapses. These changes were associated with aberrant CA1 network oscillations, pyramidal neuron bursting, and spatial information coding in vivo. Our findings relate tauopathy-associated changes in cellular neurophysiology to altered behavior-dependent network function. SIGNIFICANCE STATEMENT: Dementia is characterized by the loss of learning and memory ability. The deposition of tau protein aggregates in the brain is a pathological hallmark of dementia; and the hippocampus, a brain structure known to be critical in processing learning and memory, is one of the first and most heavily affected regions. Our results show that, in area CA1 of hippocampus, a region involved in spatial learning and memory, tau pathology is associated with specific disturbances in synaptic, cellular, and network-level function, culminating in the aberrant encoding of spatial information and spatial memory impairment. These studies identify several novel ways in which hippocampal information processing may be disrupted in dementia, which may provide targets for future therapeutic intervention.

Neurophysiological modification of CA1 pyramidal neurons in a transgenic mouse expressing a truncated form of disrupted-in-schizophrenia 1.

A t(1;11) balanced chromosomal translocation transects the Disc1 gene in a large Scottish family and produces genome-wide linkage to schizophrenia and recurrent major depressive disorder. This study describes our in vitro investigations into neurophysiological function in hippocampal area CA1 of a transgenic mouse (DISC1tr ) that expresses a truncated version of DISC1 designed to reproduce aspects of the genetic situation in the Scottish t(1;11) pedigree. We employed both patch-clamp and extracellular recording methods in vitro to compare intrinsic properties and synaptic function and plasticity between DISC1tr animals and wild-type littermates. Patch-clamp analysis of CA1 pyramidal neurons (CA1-PNs) revealed no genotype dependence in multiple subthreshold parameters, including resting potential, input resistance, hyperpolarization-activated 'sag' and resonance properties. Suprathreshold stimuli revealed no alteration to action potential (AP) waveform, although the initial rate of AP production was higher in DISC1tr mice. No difference was observed in afterhyperpolarizing potentials following trains of 5-25 APs at 50 Hz. Patch-clamp analysis of synaptic responses in the Schaffer collateral commissural (SC) pathway indicated no genotype-dependence of paired pulse facilitation, excitatory postsynaptic potential summation or AMPA/NMDA ratio. Extracellular recordings also revealed an absence of changes to SC synaptic responses and indicated input-output and short-term plasticity were also unaltered in the temporoammonic (TA) input. However, in DISC1tr mice theta burst-induced long-term potentiation was enhanced in the SC pathway but completely lost in the TA pathway. These data demonstrate that expressing a truncated form of DISC1 affects intrinsic properties of CA1-PNs and produces pathway-specific effects on long-term synaptic plasticity.

Age-related changes to Na+ channel gating contribute to modified intrinsic neuronal excitability.

Cognitive decline occurs during normal aging and is likely to be reflected in the neurophysiological properties of neural circuits with key roles in cognition, for example those of the limbic system. To identify candidate neurophysiological changes we used patch clamp methods to compare the intrinsic excitability properties of hippocampal CA1 pyramidal neurons of mature adult (8-10 month) and aged (22-24 month) mice. Resting potential, input resistance, and the "sag" observed on injection of hyperpolarizing current were not age-dependent. In contrast, the patterns of spike firing observed with depolarizing current injections demonstrated the presence of an age-related hypoexcitability. Action potential waveform analysis revealed that spike thresholds were approximately 3 mV more depolarized in aged animals. In line with this, voltage clamp recordings of Na(+) currents from nucleated macropatches exhibited an approximate 3 mV depolarizing shift in the voltage-dependence of activation gating. Inactivation curves, in contrast, were not different. These data indicate alterations in Na(+) channel activation gating contribute to neuronal hypoexcitability in aging, and therefore may be a factor in age-related cognitive decline.

Synaptic activation of mGluR1 generates persistent depression of a fast after-depolarizing potential in CA3 pyramidal neurons.

Burst firing is an important property of hippocampal pyramidal neurons. Group I metabotropic glutamate receptors (mGluRs) produce a multitude of effects on both the synaptic and intrinsic properties of neurons. We investigated whether brief activation of these receptors results in persistent modifications to the intrinsic excitability of rat hippocampal CA3 pyramidal cells (CA3-PCs). In whole-cell current-clamp recordings, current stimuli consisting of filtered, pseudo-random noise produced action potential firing with a mean frequency of ∼1.5-2 Hz. Analysis of spike intervals revealed that this firing included a substantial component (∼20%) of high-frequency (∼100 Hz) bursting activity. Activation of group I mGluRs with (S)-3,5-dihydroxyphenylglycine [(S)-DHPG] selectively eliminated the high-frequency bursts, an effect that persisted > 30 min after (S)-DHPG washout. The fast after-depolarizing potential (ADP) of CA3-PCs is known to be important for generating high-frequency action potential bursting. This ADP was persistently depressed following a short application of (S)-DHPG. This effect was blocked by the mGluR1 antagonist, (S)-(+)-α-amino-4-carboxy-2-methylbenzeneacetic acid (LY367385). In contrast, the depression was resistant to the mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate, N-methyl-D-aspartate (NMDA) and γ-aminobutyric acid (GABA)(A) antagonists. Unlike other manipulations that generate persistent depression of the ADP in CA3-PCs, DHPG-mediated ADP depression was insensitive to the Kv7 channel inhibitor 10,10-bis(4-Pyridinylmethyl)-9(10H)-anthracenone dihydrochloride (XE991) and strong intracellular Ca(2+) buffering by 1,2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). Synaptic activation of mGluRs in the associational-commissural pathway also resulted in persistent depression of the ADP in postsynaptic CA3-PCs, which was blocked by LY367385. These data represent the first evidence that synaptic activation of mGluR1 can modulate the intrinsic excitability properties of hippocampal neurons.

An ex vivo multi-electrode approach to evaluate endogenous hormones and receptor subtype pharmacology on evoked and spontaneous neuronal activity within the ventromedial hypothalamus; translation from female receptivity.

INTRODUCTION: The ventromedial hypothalamus (VMH) controls female rodent copulatory behavior, which can be modulated by injection of various compounds into the VMH. Aim. The aim was to determine whether evoked excitatory postsynaptic potentials (EPSPs) or single-unit activity within the VMH ex vivo is a better parameter to predict lordosis. METHODS: VMH slices were placed onto a 64 microelectrode chip and spontaneous single-unit activity was recorded or slices stimulated to evoke EPSPs. MAIN OUTCOME MEASURES: The sodium channel blocker, tetrodotoxin and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX) inhibited EPSPs, confirming EPSPs were glutamatergic in origin. The GABA(A) antagonist bicuculline potentiated EPSPs implying endogenous GABA tone. Single-unit activity was abolished by tetrodotoxin but unaffected by DNQX or bicuculline. RESULTS: Glutamatergic neurotransmission was greatest during metestrous and following ovariectomization. The number of regions within the VMH eliciting single-unit activity was reduced following ovariectomy without changing spike frequency. Adrenergic agents increasing lordosis via the VMH in vivo, decreased glutamate neurotransmission but increased single-unit activity. Conversely, agents decreasing lordosis via the VMH increased glutamatergic neurotransmission and inhibited single-unit activity (8-OH-DPAT, [D-Ala(2), N-Me-Phe(4), Gly-ol(5)]-enkephalin, corticotropin releasing factor, bicuculline). Melanocortin and pituitary adenylate cyclase-activating polypeptide agonists had no effect. CONCLUSIONS: Here we present a novel, robust VMH in vitro technique that (i) is consistent with the hypothesis that glutamate via non-NMDA receptors inhibits lordosis; (ii) glutamate is under the endogenous tone of GABA and steroid hormones; (iii) inhibition of lordosis during metestrous and following ovariectomy potentiates glutamatergic neurotransmission; (iv) activation of G(q)- and G(i)-coupled receptors decreases and increases glutamate neurotransmission, respectively, with an inverse correlation on single-unit activity; (v) activation of G(s)-coupled receptors has no direct effect on glutamate or single-unit activity; and (vi) potency, receptor subtypes and localization can be determined prior to in vivo studies.