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Layer V pyramidal neurons in the rat medial prefrontal cortex (PFC) were examined with whole cell patch-clamp recording in acute slices from postnatal day 1 (P1) to P36. In the first few days after birth, layer V pyramidal neurons had low resting potentials, high-input resistance, and long membrane time constant. During the next 2 wk, the resting potential shifted by -14 mV, while the input resistance and time constant decreased by 15- and 4-fold, respectively. Between P3 and P21, the surface area of the cell body doubled, while the total lengths of apical and basal dendrites increased by 5- and 13-fold, respectively. Action potentials (APs) were observed at all aged tested. The peak amplitude of APs increased by 30 mV during the first 3 wk, while AP rise time and half-maximum duration shortened significantly. Compared with neurons at P21 or older, neurons in the first week required much smaller currents to reach their maximum firing frequencies, but the maximum frequencies were lower than those at older ages. Stimulation of layer II/III induced monosynaptic responses in neurons older than P5. Paired-pulse responses showed a short-term depression at P7, which shifted progressive to facilitation at older ages. These results demonstrate that, similar to other neurons in the brain, layer V pyramidal neurons in the PFC undergo a period of rapid development during the first 3 wk after birth. These findings suggest that the intrinsic properties of neurons and the properties of synaptic inputs develop concomitantly during early life.

Dynamin-1 (Dnm1) encodes a large multimeric GTPase necessary for activity-dependent membrane recycling in neurons, including synaptic vesicle endocytosis. Mice heterozygous for a novel spontaneous Dnm1 mutation—fitful—experience recurrent seizures, and homozygotes have more debilitating, often lethal seizures in addition to severe ataxia and neurosensory deficits. Fitful is a missense mutation in an exon that defines the DNM1a isoform, leaving intact the alternatively spliced exon that encodes DNM1b. The expression of the corresponding alternate transcripts is developmentally regulated, with DNM1b expression highest during early neuronal development and DNM1a expression increasing postnatally with synaptic maturation. Mutant DNM1a does not efficiently self-assemble into higher order complexes known to be necessary for proper dynamin function, and it also interferes with endocytic recycling in cell culture. In mice, the mutation results in defective synaptic transmission characterized by a slower recovery from depression after trains of stimulation. The DNM1a and DNM1b isoform pair is highly conserved in vertebrate evolution, whereas invertebrates have only one isoform. We speculate that the emergence of more specialized forms of DNM1 may be important in organisms with complex neuronal function.

Nicotinic acetylcholine receptors are widely distributed throughout the nervous system, but their functions remain largely unknown. One of the most abundant is a class of receptors that contains the alpha 7 gene product, has a high relative permeability to calcium, and binds alpha-bungarotoxin. Here, we report that receptors sensitive to alpha-bungarotoxin, though concentrated in perisynaptic clusters on neurons, can generate a large amount of the synaptic current. Residual currents through other nicotinic receptors are sufficient to elicit action potentials, but with slower rise times. This demonstrates a postsynaptic response for alpha-bungarotoxin-sensitive receptors on neurons and suggests that the functional domain of the postsynaptic membrane is broader than previously recognized.

Synapse elimination occurs throughout the nervous system during development, and is essential for the formation of neural circuits. The mechanisms underlying synapse elimination in the brain, however, remain largely unknown. Using whole-cell patch-clamp recording in a slice preparation, we examined synaptic refinement at the somatosensory relay synapse (lemniscal synapse) in the ventral basal thalamus of the mouse during postnatal development. At 1 week old, each neuron in the ventral basal thalamus is innervated by multiple lemniscal fibres, as revealed by multiple increments of the synaptic response. By 16 days after birth (P16), the majority of neurons showed an all-or-none response, suggesting a single fibre innervation. In addition to synapse elimination, extensive modifications in synaptic properties occur during the second week after birth. The ratio of AMPA to NMDA component of the synaptic current tripled between P7 and P17. The decay constant of the NMDA component decreased by about 70% between P7 and P17; ifenprodil (3 μM) reduced the NMDA component by about 40% in neurons at P7-9, but was much less effective at P20-24. On the other hand, there was little change in the inward rectification of AMPA component between P11 and P24. Paired-pulse ratios, measured at −70 and +40 mV, were stable between P7 and P24. Whisker deprivation from P5 through P19 had no effect on the elimination or the maturation of the lemniscal synapse. These results suggest that the lemniscal synapse in the ventral basal thalamus undergoes extensive refinement during the second week, and that sensory experience has a rather limited role in this process.

Serotonin (5-HT) is widely implicated in brain functions and diseases. The vertebrate brain is extensively innervated by 5-HT fibres originating from the brain stem, and 5-HT axon terminals interact with other neurones in complex ways. The cellular mechanisms underlying 5-HT function in the brain are not well understood. The present study examined the effect of 5-HT on the responsiveness of neurones in the neocortex. Using patch-clamp recording in acute slices, we showed that 5-HT substantially increased the slope (gain) of the firing rate-current curve in layer 5 pyramidal neurones of the rat prefrontal cortex. The effect of 5-HT on gain is confined to the range of firing rate (0-10 Hz) that is known to be behaviourally relevant. 5-HT also changed current threshold for spike train generation, but this effect was inconsistent, and was independent of the effect on gain. The gain modulation by 5-HT was mediated by 5-HT 2 receptors, and involved postsynaptic mechanisms. 5-HT 2 -mediated gain increase could not be attributed to changes in the membrane potential, the input resistance or the properties of action potentials, but was associated with a reduction of the afterhyperpolarization and an induction of the slow afterdepolarization. Blocking Ca 2+ entry with Cd 2+ increased the gain by itself and blocked 5-HT 2 -mediated gain increase. Buffering [Ca 2+ ] i with 25 mM EGTA also substantially reduced 5-HT 2 -mediated gain increase. Noradrenaline, which blocked the afterhyperpolarization, also induced a moderate increase in gain. Together, our results suggest that 5-HT may regulate the dynamics of cortical circuits through multiplicative scaling. 5-HT plays an important role in the regulation of behaviour. In cats, activity of 5-HT neurones in the brain stem is highest during periods of waking arousal, decreases progressively as the animal falls asleep, and is absent during rapid-eye-movement sleep (Jacobs & Fornal, 1999). Selective depletion of 5-HT in the prefrontal cortex (PFC) of monkeys induces cognitive inflexibility (Clarke et al. 2004); and 5-HT, via 5-HT 2A receptors, has been shown to contribute to working memory in the monkey PFC (Williams et al. 2002). In humans, dysfunction of the brain 5-HT system plays a critical role in depression; and many antidepressants are selective 5-HT uptake blockers, which enhance 5-HT transmission in the brain (Blier & de Montigny, 1999;Delgado, 2000;Bell et al. 2001). Together, such evidence suggests that at the system level, 5-HT facilitates motor and other executive functions of the CNS.The cellular mechanisms underlying brain 5-HT function are not well understood. Early in vivo studies showed that the predominant effect by 5-HT in the cerebral cortex is an inhibition of spontaneous firing (Krnjevic & Phillis, 1963;Reader et al. 1979). Later studies using intracellular recordings in brain slices revealed that 5-HT induces, often in the same cell, both inhibitory and excitatory responses (Segal, 1980;Andrade & Nicoll, 1987;Araneda & Andrade, 1991;Tanaka & North, 1993;Spain...

Methyl-CpG binding protein 2 (MeCP2) is highly expressed in neurons in the vertebrate brain, and mutations of the gene encoding MeCP2 cause the neurodevelopmental disorder Rett syndrome. This study examines the role of MeCP2 in the development and function of thalamic GABAergic circuits. Whole cell recordings were carried out in excitatory neurons of the ventrobasal complex (VB) of the thalamus and in inhibitory neurons of the reticular thalamic nucleus (RTN) in acute brain slices from mice aged P6 through P23. At P14-P16, the number of quantal GABAergic events was decreased in VB neurons but increased in RTN neurons of Mecp2-null mice, without any change in the amplitude or kinetics of quantal events. There was no difference between mutant and wild-type mice in paired-pulse ratios of evoked GABAergic responses in the VB or the RTN. On the other hand, unitary responses evoked by minimal stimulation were decreased in the VB but increased in the RTN of mutants. Similar changes in the frequency of quantal events were observed at P21-P23 in both the VB and RTN. At P6, however, quantal GABAergic transmission was altered only in the VB not the RTN. Immunostaining of vesicular GABA transporter showed opposite changes in the number of GABAergic synaptic terminals in the VB and RTN of Mecp2-null mice at P18-P20. The loss of MeCP2 had no significant effect on intrinsic properties of RTN neurons recorded at P15-P17. Our findings suggest that MeCP2 differentially regulates the development of GABAergic synapses in excitatory and inhibitory neurons in the thalamus.