Routh BN, Johnston D, Harris K, Chitwood RA. Anatomical and electrophysiological comparison of CA1 pyramidal neurons of the rat and mouse. J Neurophysiol 102: 2288 -2302, 2009. First published August 12, 2009 doi:10.1152/jn.00082.2009. The study of learning and memory at the single-neuron level has relied on the use of many animal models, most notably rodents. Although many physiological and anatomical studies have been carried out in rats, the advent of genetically engineered mice has necessitated the comparison of new results in mice to established results from rats. Here we compare fundamental physiological and morphological properties and create three-dimensional compartmental models of identified hippocampal CA1 pyramidal neurons of one strain of rat, SpragueDawley, and two strains of mice, C57BL/6 and 129/SvEv. We report several differences in neuronal physiology and anatomy among the three animal groups, the most notable being that neurons of the 129/SvEv mice, but not the C57BL/6 mice, have higher input resistance, lower dendritic surface area, and smaller spines than those of rats. A surprising species-specific difference in membrane resonance indicates that both mouse strains have lower levels of the hyperpolarization-activated nonspecific cation current I h . Simulations suggest that differences in I h kinetics rather than maximal conductance account for the lower resonance. Our findings indicate that comparisons of data obtained across strains or species will need to account for these and potentially other physiological and anatomical differences.

Despite the critical importance of voltage-gated ion channels in neurons, very little is known about their functional properties in Fragile X syndrome: the most common form of inherited cognitive impairment. Using three complementary approaches, we investigated the physiological role of A-type K ϩ currents (I KA ) in hippocampal CA1 pyramidal neurons from fmr1-/y mice. Direct measurement of I KA using cell-attached patch-clamp recordings revealed that there was significantly less I KA in the dendrites of CA1 neurons from fmr1-/y mice. Interestingly, the midpoint of activation for A-type K ϩ channels was hyperpolarized for fmr1-/y neurons compared with wild-type, which might partially compensate for the lower current density. Because of the rapid time course for recovery from steady-state inactivation, the dendritic A-type K ϩ current in CA1 neurons from both wild-type and fmr1-/y mice is likely mediated by K V 4 containing channels. The net effect of the differences in I KA was that back-propagating action potentials had larger amplitudes producing greater calcium influx in the distal dendrites of fmr1-/y neurons. Furthermore, CA1 pyramidal neurons from fmr1-/y mice had a lower threshold for LTP induction. These data suggest that loss of I KA in hippocampal neurons may contribute to dendritic pathophysiology in Fragile X syndrome.

Fragile X syndrome is the most common form of inherited mental impairment and autism. The prefrontal cortex is responsible for higher order cognitive processing, and prefrontal dysfunction is believed to underlie many of the cognitive and behavioural phenotypes associated with fragile X syndrome. We recently demonstrated that somatic and dendritic excitability of layer (L) 5 pyramidal neurons in the prefrontal cortex of the fmr1 mouse is significantly altered due to changes in several voltage-gated ion channels. In addition to L5 pyramidal neurons, L2/3 pyramidal neurons play an important role in prefrontal circuitry, integrating inputs from both lower brain regions and the contralateral cortex. Using whole-cell current clamp recording, we found that L2/3 pyramidal neurons in prefrontal cortex of fmr1 mouse fired more action potentials for a given stimulus compared with wild-type neurons. In addition, action potentials in fmr1 neurons were significantly larger, faster and narrower. Voltage clamp of outside-out patches from L2/3 neurons revealed that the transient Na current was significantly larger in fmr1 neurons. Furthermore, the activation curve of somatic A-type K current was depolarized. Realistic conductance-based simulations revealed that these biophysical changes in Na and K channel function could reliably reproduce the observed increase in action potential firing and altered action potential waveform. These results, in conjunction with our prior findings on L5 neurons, suggest that principal neurons in the circuitry of the medial prefrontal cortex are altered in distinct ways in the fmr1 mouse and may contribute to dysfunctional prefrontal cortex processing in fragile X syndrome.

Highlights d Neurons in behaving macaque V1 exhibit a large voltagegated intrinsic conductance d This conductance leads to an increase in membrane resistance with depolarization d This mechanism increases neuronal gain and selectivity to subthreshold depolarization d This nonlinearity should be incorporated into future models of cortical computations

Circadian clocks confer 24-h periodicity to biological systems, to ultimately maximize energy efficiency and promote survival in a world with regular environmental light cycles. In mammals, circadian rhythms regulate myriad physiological functions, including the immune, endocrine, and central nervous systems. Within the central nervous system, specialized glial cells such as astrocytes and microglia survey and maintain the neuroimmune environment. The contributions of these neuroimmune cells to both homeostatic and pathogenic demands vary greatly across the day. Moreover, the function of these cells changes across the lifespan. In this review, we discuss circadian regulation of the neuroimmune environment across the lifespan, with a focus on microglia and astrocytes. Circadian rhythms emerge in early life concurrent with neuroimmune sculpting of brain circuits and wane late in life alongside increasing immunosenescence and neurodegeneration. Importantly, circadian dysregulation can alter immune function, which may contribute to susceptibility to neurodevelopmental and neurodegenerative diseases. In this review, we highlight circadian neuroimmune interactions across the lifespan and share evidence that circadian dysregulation within the neuroimmune system may be a critical component in human neurodevelopmental and neurodegenerative diseases.

Many neuronal cell types exhibit a sliding scale of neuronal excitability in the subthreshold voltage range. This is due to a variable contribution of different voltage-gated ion channels leading to a scaling of input resistance (RN) as a function of membrane potential (Vm) and a voltage-dependent dynamic gain of neuronal responsiveness. In layer 2/3 pyramidal neurons within the primary visual cortex (V1), this response influences sensory processing by tightening neuronal tuning to preferred orientations, but the identity of the ionic conductances involved remain unknown. Here we used in vitro physiological recordings in acute slices to identify the contributions of several voltage-dependent conductances to the dynamic gain of membrane responses in layer 2/3 pyramidal neurons in mouse primary visual cortex. We found that the steep voltage-dependence of input resistance in these cells was mediated in part by a combination of persistent sodium, inwardly-rectifying potassium, and hyperpolarization-activated nonselective cation channels. Additionally, the steepness of the slope of the RN/Vm relationship was inversely correlated with the number of branches on the proximal apical dendrite. These data have uncovered physiological and morphological factors that underlie the scaling of membrane responses in L2/3 neurons of rodent V1. Regulation of these channels would serve as a mechanism of real time neuro-modulation of neuronal processing of sensory information.